CN101534644B - Process for preparing pyridinamines and novel polymorphs thereof - Google Patents
Process for preparing pyridinamines and novel polymorphs thereof Download PDFInfo
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Abstract
The present invention relates to an improved process for the synthesis and purification of 3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)-a,a,a-trifluoro-2,6-dinitro-p-toluidine (fluazinam) and other pyridinamines, which implements methyl isobutyl ketone (MIBK) as the reaction solvent. The process of the invention overcomes the drawbacks of prior art methods, by reducing the side reactions such as hydrolysis, eliminating the need for difficult and labor-intensive purification methods, and providing pure products in higher yields. The present invention relates to novel crystalline polymorphic forms fluazinam, and to mixtures of the polymorphs. The present invention also provides methods for preparing the novel polymorphs, as well as pharmaceutical compositions comprising same, and methods of using the polymorphs as pesticidal agents for combating noxious living organisms on agricultural and horticultural crops.
Description
Invention field
The present invention relates to the synthetic of pyridine amine, and relate more particularly to improved synthetic method to N-phenylpyridine amine, described amine for example-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)-α, α, α-three fluoro-2,6-dinitrobenzene-para-totuidine (fluazinam (fluazinam)), a kind of sterilant.The present invention relates to the new crystallization polymorph of fluazinam, its preparation method, the composition that contains this polymorph with and as the application of sterilant.
Background of invention
Some pyridine amine with insecticidal activity can be used for resisting harmful biology, for example insect, acarid, fungi, bacterium and rodent.For example US Patent No. 4,140, disclose in 778 to have the active compound that kills mouse, and in US Patent No. 3,965, disclose the compound with insecticidal activity in 109 and US3,926,611.
US Patent No. 4,331,670 is open and required protection to the N-pyridine amine that has special substituent at pyridine ring.These compounds are used for resisting Industrial products, the insect that the storage of seed and fruit is harmful, acarid, fungi, bacterium and rodent and be effective in the growth of controlling harmful organism aspect agricultural and gardening farm crop and the highland.One of these compounds, the fluazinam at present marketization are used for administering the sclerotinite maize ear rot, and the latter is a kind of principal disease of lettuce, is to give birth to fungus-caused by two kinds of earth: sclerotinia species and sclerotinite.Fluazinam and other sterilant be boscalid amine (boscalid) for example, and fenhexamid (fenhexamid) and fludioxonil (fludioxonil) also demonstrate effectiveness in opposing aspect sclerotinia species and the microbial disease of agricultural plants except lettuce of nuclear disk.
People have also recognized 3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)-α, α, α-three fluoro-2,6-dinitrobenzene-para-totuidine (fluazinam) helps the Aucubaceae plant of container nursery to avoid southern blight, the latter is a kind of harmful disease in hot day, can be to the arbor that blooms of nursery and greening usefulness, shrub, and the draft decorative plant has a negative impact.
Fluazinam has broad-spectrum antibacterial action and plant disease is shown good prophylactic effect.Fluazinam is showing good activity aspect the botrytis cinerea with benzoglyoxaline and/or dicarboximide resistance.The field test chart understands the activity of fluazinam excellence aspect anti-potato phytophthora (Phycophthorainfestan).By to the field re-treatment, fluazinam also shows the quantity that can significantly reduce acarid.(ACS Symposium Series 1995584，443-8)。
US Patent No. 4,331,670 content is all incorporated by reference at this, wherein discloses the coupling process of the pyridine amine of preparation example in the following manner such as fluazinam.
This reaction utilizes THF or DMF as solvent, 75% and 22% the productive rate that obtains respectively reporting.Aforesaid solvent is so that reaction is subject to many disadvantageous effects.For example, THF is a kind of flammable non-security solvent, and its flash-point is lower and be the source that superoxide forms; Therefore its large-scale application is extremely restricted.In addition, for example the aprotic solvent of THF and DMF is to contain a large amount of water with water miscibility and azeotrope that be used for circulation.The existence of water has reduced the productive rate of reaction, is owing to not completely consumed of reactant on the one hand, on the other hand because the generation of hydrolysising by-product.For example, by product that competitive side reaction is compound (1A) production (4) in the presence of water.This reaction has significantly reduced the productive rate of final product.
In addition, method of the prior art comprises very loaded down with trivial details reprocessing step, comprise be extracted in the 3rd solvent-ethyl acetate and in silica gel purifying, this all is not suitable for scale operation.These complicated purification steps for remove a large amount of impurity of in reaction, forming for example the said hydrolyzed product be essential, accelerate two kinds of reactants (1A) of the tar that forms and not completely consumed and (2A) also be essential (mainly being to react owing to the reactant that is less than 8.2%w/v under diluting condition is delivered to solvent) for removing in the temperature that is higher than 40 ℃.
Up to the present, still simply not being used for the method for purifying fluazinam can be used in the highly purified fluazinam of scale operation.Also nobody understands the fluazinam of crystallization polymorph form.Therefore technically active demand is prepared effective ways with purifying to fluazinam and other pyridine amine, and the method can overcome unfavorable factor of the prior art and defective.
Summary of the invention
The present invention relates to Innovative method for the synthesis of 3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)-α, α, α-three fluoro-2,6-dinitrobenzene-para-totuidine (fluazinam) and other pyridine amine, and use mibk (MIBK) as reaction solvent.Method of the present invention has overcome unfavorable factor of the prior art by the side reaction that reduces for example hydrolysis, has eliminated for the not only demand of the purification process of difficulty but also effort, and the purer product of high yield is provided.On the other hand, the present invention relates to the fluazinam of new crystallization polymorph form, and the mixture of these polymorphs.The present invention also provides preparation New Polycrystalline shape thing and has contained the method for the insecticides of this polymorph, and use this polymorph as sterilant resist to agricultural and gardening farm crop be harmful to biological aspect using method.
As this concern, applicant of the present invention is surprised to find that when using MIBK to be used for preparing fluazinam and other pyridine amine as reaction solvent can provide more effective means, and the method has reduced labour intensity and greatly improved productive rate and the purity of pyridine amine product.This means using THF and DMF to improve as a far reaching of the method for solvent in the prior art.At first, 22% and when the using THF 75% of chemical yield when using DMF brings up to about 98%.In addition, method of the present invention replaces heavy tower purification step so that the reprocessing step is more simple and easy to do by simple crystallisation step.
Wish is not arrested in any special mechanism or theory, is considered to the advantage that several advantageous properties by MIBK produce and comprises: 1) be easy to recirculation and improved security; 2) compare the lower water content of recirculation solvent (1.6%) with THF water content (5%); 3) low water-soluble and 4) susceptibility that temperature fluctuation is reduced.The low water solubility of MIBK is to be present in the water yield of reaction process minimum, thereby reduced the amount of hydrolysising by-product and increased productive rate.The susceptibility that temperature fluctuation is reduced is important, especially because react very exothermic, and at high temperature produces a large amount of tar.
In addition, a unfavorable factor in the method for prior art is two kinds of reactants (1A) and incomplete consumption (2A), mainly is because reaction is to carry out under the condition that is diluted (being less than the reactant of 8.2 weight/volume (w/v) to solvent).Especially, when using for example THF, when the solvent of DMF or other water-soluble solvent, reaction can not be carried out under concentrated condition, because produce in the reaction and the water that is present in the high density in the reactant can increase the amount of hydrolysising by-product, reduces thus productive rate.When using MIBK to make solvent, do not find this phenomenon, low water-soluble mainly due to it.In fact, the applicant is surprised to find that reaction is more concentrated, and it is fewer to observe hydrolysis reaction.The use of MIBK allows to react under more concentrated condition thus to be carried out, and has greatly increased the efficient of reaction.
The solvent Chinese style A that refers at the per unit volume of reaction mixture as term " reactant is to solvent ratio " as used herein and B (or formula 1 and 2 or formula 1A and 2A) the gross weight of reactant, with weight percent (W/V) expression of per unit volume.In a kind of embodiment, reactant is at least about 10% to solvent ratio.Preferably, reactant is at least about 25% to solvent ratio, more preferably is at least about 40% weight/volume (W/V).
Therefore, one of purpose of the present invention provides a kind of new method of the pyridine amine compound for the preparation of representing with structural formula (I).
Wherein X is trifluoromethyl group, halogen atom, C
1-C
6Alkyl group or C
1-C
6Alkoxy base; N is the integer between 0-4, and R is hydrogen atom or acetyl group; Y is hydrogen atom, halogen atom, C
1-C
6Alkoxy base, C
1-C
6Alkylthio (thioalkyl) group, alkyl sulfide group, oh group, azido-group, the phenoxy group group that phenoxy group group or phenyl are replaced by hydroxyl; And Z
1, Z
2And Z
3Respectively trifluoromethyl group or nitryl group.
According to method of the present invention, these pyridine amine are so synthetic, the compound of formula (A) compound with formula (B) is reacted in the situation of alkali existence, its Chinese style (A) and (B) in X, Y, Z
1, Z
2, Z
3With n as defined above, and among U and the W one is amino and another is leaving group, for example halogen, alkyl sulphonyl, aryl sulfonyl, wherein MIBK is as reaction solvent.
In one embodiment, MIBK is as neat solvent.Term " neat solvent " refers to the purity at least about 98% as used herein.In another embodiment, MIBK is at least about 99% purity.In another embodiment, MIBK is at least about 99.5% purity.In another embodiment, MIBK is at least about 99.8% purity.In another embodiment, use the moisture MIBK that is less than about 2% circulation.A kind of preferred embodiment in, use the circulation azeotrope of moisture 1.6% MIBK.
In another embodiment; the invention provides a kind of method for the preparation of the pyridine amine that is called as fluazinam with formula (3) expression; it is by in the situation about existing at alkali reacting the compound of formula (1) and the compound of formula (2); wherein among U and the W is amino and another is leaving group; be selected from halogen; alkyl sulphonyl and aryl sulfonyl use MIBK as reaction solvent.
This process is carried out in alkali, is preferably selected from alkali metal hydroxide, alkaline carbonate, hydride, alkaline earth metal hydroxides and alkaline earth metal carbonate.
A kind of preferred embodiment in, alkali is potassium hydroxide or sodium hydroxide.
In another embodiment, the invention provides the method for the preparation of the pyridine amine that is called as fluazinam of formula (3) expression, is with the compound of formula (1A) and the compound reaction of formula (2A), uses MIBK as reaction solvent.
This process is carried out in alkali, is preferably selected from alkali metal hydroxide, alkaline carbonate, hydride, alkaline earth metal hydroxides and alkaline earth metal carbonate.
A kind of preferred embodiment in, alkali is potassium hydroxide or sodium hydroxide.
Another object of the present invention provides the method for the compound of purifying formula (I) expression, and the method comprises the step of the described compound of crystallization from the mixture of solvent or solvent.Preferred with an organic solvent or the mixture of multiple organic solvent be used for crystallization.Preferred organic solvent is ethanol in crystallisation step.
The present invention also has the another one purpose to provide method for the purifying fluazinam, and the method comprises the step of the described compound of crystallization from the mixture of solvent or solvent.Preferred organic solvent is ethanol in crystallisation step.As this concern, crystallization method described herein may cause forming the New Polycrystalline shape thing form of fluazinam, or its mixture.Therefore these polymorph forms or mixture also consist of part of the present invention.
Thus, from another aspect, the invention provides the fluazinam of New Polycrystalline shape thing form, and preparation method thereof.In one embodiment, the invention provides the new crystallization polymorph form of fluazinam, be called as " form I ".Form I has roughly X-ray powder diffraction figure as shown in Figure 1, and it has the characteristic peak (with angle 2 θ (+/-0.2 ° of θ) expression) in following one or more positions: 8.7,10,12.0,13.7,14.5,17.4,18.5,19.7,21.8,22.9 and 30.2.Form I also have as shown in Figure 2 at 3000cm
-1Infrared spectrum, at about 3390cm
-1Near have characteristic peak.Form I also has roughly means of differential scanning calorimetry (DSC) graphic representation as shown in Figure 3, when adopting differential scanning calorimeter with the velocity sweeping of 10 ℃ of per minutes, it is characterized in that occurring main endotherm(ic)peak near about 115.5 ℃.Form I is usually with the form crystallization of prism, and typical large yellow as described herein is prismatic.
In another embodiment, the invention provides the new crystallization polymorph form of fluazinam, be called as " form II ".Form II has roughly X-ray powder diffraction figure as shown in Figure 4, and it has the characteristic peak (with angle 2 θ (+/-0.2 ° of θ) expression) in following one or more positions: 7.4,10.4,13.4,15.1,18.95,20,20.4,21.05,21.3,22.2,24.9,27.15,28.6 and 30.5.Form II also have as shown in Figure 5 at 3000cm
-1Infrared spectrum, at about 3375cm
-1Near have characteristic peak.Form II also has roughly DSC graphic representation as shown in Figure 6, when adopting differential scanning calorimeter with the velocity sweeping of 10 ℃ of per minutes, it is characterized in that occurring main endotherm(ic)peak near about 109 ℃.Form II is typically bright yellow spicule usually with the form crystallization of spicule.
In another embodiment, the invention provides the polymorph form I of fluazinam and the mixture of form II.This mixture has roughly X-ray powder diffraction figure as shown in Figure 7, roughly as shown in Figure 8 at 3000cm
-1Infrared spectrum, and as shown in Figure 9 DSC graphic representation roughly adopts differential scanning calorimeter with the velocity sweeping of 10 ℃ of per minutes.
On the other hand, the invention provides the method for the preparation of the New Polycrystalline shape thing of fluazinam form I and form II, and the method for the mixture of preparation polymorph.
In one embodiment, the fluazinam of form I can prepare like this: from being selected from ethanol, acetonitrile, crystallization fluazinam in the solvent of methylene dichloride and normal hexane; And separate the crystal obtain.A kind of preferred embodiment in, the method comprises the preparation solution of this compound in one or more above-mentioned solvents, preferably heating is until fully dissolving, then cooling solution separates this crystallization until crystallization occurs.
In another embodiment, the fluazinam of form I and form II can prepare by going out fluazinam with the crystallization from ether of different crystallization conditions.In order to prepare form I, fluazinam is dissolved in the ether, preferably at room temperature, and flask is exposed to solvent is slowly volatilized.Begin gradually to occur crystallization, then normally large yellow prism shape separates this crystallization.When preparing form II, also as mentioned above with compound dissolution in ether, but make solvent from flask fast the volatilization.This can cause the formation of crystallization, and then normally bright yellow spicule separates this crystallization.
In another embodiment, form II can prepare like this, prepares the ethanolic soln of fluazinam by the mode of form I as mentioned above.Yet, be not to be settled out product by cooling, but solution be exposed in the environment, thereby so that partial solvent slowly volatilize.Begin gradually to occur crystallization, then normally bright yellow spicule separates this crystallization.
In another embodiment, the mixture of form I and form II prepares like this, and from being selected from Virahol, then crystallization fluazinam in the solvent of normal hexane and toluene separates the crystallization that obtains.A kind of preferred embodiment in, the method comprises the preparation solution of fluazinam in one or more above-mentioned solvents, preferably heating until fully dissolving cool off this solution until crystallization occurs, and separate this crystallization.
The mixture of form I and form II also can prepare like this, and fluazinam is dissolved in the soluble solvent of described compound, adds anti-solvent, and separates the crystallization that obtains.A kind of preferred embodiment in, solvent is acetone.In another preferred embodiment, anti-solvent is water.
On the other hand, the invention provides the insecticides that comprises new crystallization polymorph, it can be used for controlling and resist for example insect of the harmful organism that grows, acarid, fungus and bacterium aspect agricultural and gardening farm crop and highland.In one embodiment, said composition comprises the fluazinam of the polymorph form I of crystallization; And acceptable auxiliary (adjuvant).In another embodiment, said composition comprises the fluazinam of the polymorph form II of crystallization; And acceptable auxiliary.In another embodiment, said composition comprises the mixture of the fluazinam of the polymorph form I of crystallization and form II; And acceptable auxiliary.
The invention still further relates to and resist insect, acarid, the method for fungus and bacterium is by contact insect, acarid, fungus and bacterium or be exposed in the present composition of effective dose.
The invention still further relates to the method on protection farm crop and highland, comprise the Industrial products that obtain thus, for example seed and fruit are by apply the composition of the present invention of effective dose to farm crop or product.
By detailed description hereinafter, the four corner of further embodiment of the present invention and application will become obvious.But, be to be understood that to represent the detailed description of the preferred embodiment for the present invention and special embodiment, provide for illustrative purposes only usefulness at this, for a person skilled in the art, various changes and modifications within the spirit and scope of the present invention will be obvious.
Brief description
Fig. 1 is the X-ray powder diffraction figure of fluazinam form I.
Fig. 2 is that the FT infrared spectrum of fluazinam form I is (at 3000cm
-1Scope).
Fig. 3 is means of differential scanning calorimetry (DSC) graphic representation of fluazinam form I.
Fig. 4 is the X-ray powder diffraction figure of fluazinam form II.
Fig. 5 is that the FT infrared spectrum of fluazinam form II is (at 3000cm
-1Scope).
Fig. 6 is means of differential scanning calorimetry (DSC) graphic representation of fluazinam form II.
Fig. 7 is the X-ray powder diffraction figure of the mixture of fluazinam form I and form II.
Fig. 8 is that the FT infrared spectrum of mixture of fluazinam form I and form II is (at 3000cm
-1Scope).
Fig. 9 is means of differential scanning calorimetry (DSC) graphic representation of the mixture of fluazinam form I and form II.
Detailed Description Of The Invention
On the one hand, the present invention relates to for the synthesis of 3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)-α, α, α-three fluoro-2, improving one's methods of 6-dinitrobenzene-para-totuidine (fluazinam) and other pyridine amine, it uses mibk (MIBK) as reaction solvent.Method of the present invention has overcome unfavorable factor of the prior art by the side reaction that reduces for example hydrolysis, has eliminated for the not only demand of the purification process of difficulty but also effort, and the pure product of high yield is provided.
Wish is not arrested in any special mechanism or theory, it is believed that, although need water in the reprocessing step of reaction, when coming product separation by acidifying, be negative role in the coupled reaction of water between compd A and compd B particularly.Especially, it is believed that water can cause the incomplete consumption of reactant by producing hydrolysising by-product.The introducing of water has three different sources: the water that the hydrochloric acid that 1) discharges by neutralization produces by stoichiometry; 2) water that contains 10-15% in for example KOH that uses in the reaction and the solid-state mineral alkali of NaOH; 3) use as with the water-miscible solvent of the recirculation of the azeotrope of water THF for example, DMF and DMSO introduce water.
For avoiding these problems, the reaction in the prior art in THF or DMF is to carry out under the condition of extremely dilution, in order to make the concentration of water minimum.But this can cause the remarkable reduction of reaction yield and efficient.
As in this concern, the applicant has screened several different water miscible solvents that have, be used for synthesize fluazinam and other pyridine amine according to scheme mentioned above as reaction solvent.Table 1 has represented the physical parameter of several test solvent.
Table 1: the physical parameter of several useful solvents
The applicant is surprised to find, and MIBK is the superior solvent for coupled reaction.MIBK is distilled as 76% solvent azeotrope.But, lower water-soluble because of it, after leaving standstill, be divided into two-layerly, rich organic matter layer contains 98.40% the MIBK of having an appointment, and water-enriched layer contains 1.6% the MIBK of having an appointment.MIBK is in several solvents of research, unique water content (24%) in its azeotrope and the remarkable different solvent of water content (1.6%) in its recirculation solvent.
Wish is not arrested in any special mechanism or theory, and people at least in part, owing to its unique character, comprise low water content in its low water-soluble and recirculation solvent with the advantage of MIBK as reaction solvent.
By only allowing minimum " effectively water " disturbance reponse, MIBK is found to be and overcomes too much aquatic debatable optimum solvent.To react the low water solubility of the MIBK that comes with too much water shielding, can be used for more concentrated system.This all is optimal for the chemical yield that improves scale operation and volume productivity.Certain, chemical yield is improved to 98% from 75%, and volume productivity (being that reactant is to solvent ratio) is improved at least about 40%w/v from 8.2%.
Another advantage of using MIBK is that the known of MIBK is compared to the much lower susceptibility of temperature fluctuation with other solvent phase.This is very important, because react very exothermic and at high temperature can produce a large amount of tar.Replace tower purifying that reprocessing is more prone to as solvent by simple crystallization with MIBK.
Therefore an object of the present invention is to provide new method, the method is used very effective solvent in the pyridine amine compound that preparation represents with structural formula (I).
Wherein X is trifluoromethyl group, halogen atom, C
1-C
6Alkyl group or C
1-C
6Alkoxy base; N is 0,1,2,3 or 4 integer, and R is hydrogen atom or acetyl group; Y is hydrogen atom, halogen atom, C
1-C
6Alkoxy base, C
1-C
6The alkylthio group, oh group, azido-group, phenoxy group group or the phenoxy group group that replaced by hydroxyl of phenyl wherein; And Z
1, Z
2And Z
3Trifluoromethyl group or nitryl group independently.
According to method of the present invention, these pyridine amine are so synthetic, the compound of formula (A) compound with formula (B) is reacted in the situation of alkali existence, its Chinese style (A) and (B) in X, Y, Z
1, Z
2, Z
3With n as defined above, and among U and the W one is amino and another is leaving group, is selected from halogen, alkyl sulphonyl, aryl sulfonyl, wherein MIBK is as reaction solvent.In one embodiment, use MIBK as neat solvent.In another embodiment, use the recirculation azeotrope of moisture about 1.6% MIBK.
Term " C
1-C
6Alkyl group " use separately or represent straight chain as the part of another group at this; side chain or annular (for example cycloalkyl); saturated or unsaturated (thiazolinyl for example; alkynyl) group; the latter only when the carbon atom number of alkyl chain more than or equal to 2 the time, and can comprise mixed structure.The example of saturated alkyl group includes but not limited to methyl, ethyl, and n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, tert-pentyl, hexyl, etc.The example of alkenyl group comprises vinyl, allyl group, butenyl etc.The example of alkynyl group comprises ethynyl, proyl etc.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
C
1-C
6Alkyl group can be non-substituted, also can be replaced by one or more substituting groups, and substituting group is selected from hydroxyl, alkoxyl group; aryloxy, alkyl-aryloxy, heteroaryloxy, oxo (oxo); cycloalkyl, phenyl, heteroaryl, heterocyclic radical; naphthyl, amino, alkylamino, virtue is amino; assorted virtue is amino, dialkylamino, and diarylamino, the alkyl virtue is amino; the assorted virtue of alkyl is amino, and the assorted virtue of aryl is amino, acyl group; acyloxy, nitro, carboxyl; formamyl, amide group (carboxamide), cyano group; alkylsulfonyl, sulfonamido, sulfinyl; sulfonamido, sulfydryl, C
1-C
6Alkylthio arylthio, or C
1-C
6The alkyl sulphonyl group.Any substituting group can be non-substituted or further be replaced by arbitrary aforementioned substituting group.
Term " aryl " uses or represents to contain as the part of another group separately the aromatic nucleus system of 6-14 ring carbon atom at this.Aryl rings can be monocycle, dicyclo, and three rings, etc.The nonrestrictive example of aryl has phenyl, and naphthyl comprises 1-naphthyl and 2-naphthyl, etc.This aryl can be non-substituted, also can be replaced by one or more aforesaid alkyl substituents.
Term " C
1-C
6Alkoxyl group " at this C described above that uses separately or represent as the part of another group to connect with Sauerstoffatom
1-C
6Alkyl.The example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy etc.Term " phenoxy group " is at this phenyl that uses separately or represent as the part of another group to connect with Sauerstoffatom.C
1-C
6Alkoxyl group or phenoxy group can be non-substituted, also can be replaced by one or more aforesaid alkyl substituents.
Term " C
1-C
6Alkylthio " at this C described above that uses separately or represent as the part of another group to connect with sulphur atom
1-C
6Alkyl.The nonrestrictive example of alkylthio has sulphomethyl, thio-ethyl, sulfo-n-propyl, sulfo-sec.-propyl, sulfo-normal-butyl, sulfo-tertiary butyl etc.C
1-C
6Alkylthio can be non-substituted, also can be replaced by one or more aforesaid alkyl substituents.
Term " trifluoromethyl " uses separately or represents CF as the part of another group at this
3Group.Term " hydroxyl " uses separately or represents the OH group as the part of another group at this.Term " halogen " or " halogen " use separately or represent chlorine, bromine, fluorine and iodine as the part of another group at this.Term " azido-" uses separately or represents N as the part of another group at this
3Group.Term " ethanoyl " uses separately or represents COCH as the part of another group at this
3Group.Term " nitro " uses separately or represents NO as the part of another group at this
2Group.Term " amino " uses separately or represents NH as the part of another group at this
2Group.Term " alkylsulfonyl " uses separately or represents-S (O) as the part of another group at this
2-.The alkyl sulphonyl base refers to that the alkylsulfonyl upper joint has alkyl group described above.The aryl sulfonyl base refers to that the alkylsulfonyl upper joint has aromatic yl group described above.
In another embodiment; the present invention also provides for the preparation of the method suc as formula the fluazinam shown in (3); by in the situation about existing at alkali the compound of formula (1) and the compound of formula (2) being reacted; wherein among U and the W is amino and another is leaving group; be selected from halogen; alkyl sulphonyl, aryl sulfonyl, wherein MIBK is as reaction solvent.
Method of the present invention is carried out in alkali.Preferably, alkali is selected from alkali metal hydroxide (for example sodium hydroxide, potassium hydroxide), alkaline carbonate (sodium bicarbonate for example, yellow soda ash, yellow soda ash, salt of wormwood), hydride (sodium hydride for example, potassium hydride KH), alkaline earth metal hydroxides (for example magnesium hydroxide, calcium hydroxide) and alkaline earth metal carbonate (for example magnesiumcarbonate, calcium carbonate).Preferred alkali is potassium hydroxide or sodium hydroxide.
Preferably, reactant to solvent ratio greater than about 10%w/v.More preferably, reactant to solvent ratio greater than about 25%w/v, and most preferably, reactant to solvent ratio greater than about 40%w/v.This with now under the reaction conditions of dilution (less than the reactant of 8.2%w/v to solvent ratio), caused reactant (A) with (B) in the method for technology thus reaction not exclusively the reduction productive rate compare and had advantage.
In another embodiment, the invention provides the method for the preparation of the pyridine amine that is called as fluazinam (shown in (3)), be by with the compound of formula (1A) and the compound reaction of formula (2A), use MIBK to make reaction solvent.
Method of the present invention is carried out in alkali.Preferably, alkali is selected from alkali metal hydroxide (for example sodium hydroxide, potassium hydroxide), alkaline carbonate (sodium bicarbonate for example, yellow soda ash, yellow soda ash, salt of wormwood), hydride (sodium hydride for example, potassium hydride KH), alkaline earth metal hydroxides (for example magnesium hydroxide, calcium hydroxide) and alkaline earth metal carbonate (for example magnesiumcarbonate, calcium carbonate).Preferred alkali is potassium hydroxide or sodium hydroxide.
Preferably, reactant to solvent ratio greater than about 10%w/v.More preferably, reactant to solvent ratio greater than about 25%w/v, and most preferably, reactant to solvent ratio greater than about 40%w/v.This with now under the reaction conditions of dilution (less than the reactant of 8.2%w/v to solvent ratio), caused reactant (A) with (B) in the method for technology thus reaction not exclusively the reduction productive rate compare and had advantage.
Preferred solvent is pure MIBK (for example at least about 98% purity) or the moisture MIBK that is lower than 2% recirculation in this new method.Moisturely preferably be lower than approximately 1.9%, more preferably less than about 1.75%, most preferably be lower than about 1.6%.A kind of preferred embodiment in, use the recirculation azeotrope of moisture about 1.6% MIBK.The low water solubility feature of MIBK allows reaction to carry out under more concentrated condition, has increased significantly the efficient of reaction.
Generally speaking, because the exothermic character of coupled reaction, the temperature of reaction is maintained at about 0-20 ℃ or lower in about first hour.Then, reaction can rise to room temperature (about 25-30 ℃), and stirs under this temperature until reaction is finished, usually from about 2-3 hour to about 24 hours.Reprocessing (work-up) comprises acidifying, for example adds to resemble HCl or H
2SO
4Acid.Form the mixture of two-phase.Then separate organic layer, after vaporing away solvent, isolate product.
The purifying of the compound of formula (I) is by from the mixture of a kind of solvent or multi-solvents, and preferably this mixture of crystallization is finished from the mixture of organic solvent or multiple organic solvent.Thus, in one embodiment, the invention provides the compound that a kind of method is used for purifying formula (I), is to finish by this mixture of crystallization from the mixture of a kind of solvent or multi-solvents.In one embodiment, the compound of formula (I) is the fluazinam by structural formula (3) expression.Preferred organic solvent is ethanol in the crystallisation step.The ethanol of applicable grade comprises the ethanol of 80-100%.Ethanol can be that wet or dried.
Crystallization can be finished like that according to well known in the prior art, for example passes through required compound in an amount of solvent or solvent mixture, and heating makes its dissolving, and cooling makes the product precipitation.Selectively, compound dissolution in a kind of solvent, and is added the insoluble or sl. sol. solvent of the second compound, until precipitation occurs.As well known in the prior art, reaction can also use suitable compound crystal seed as seed with induced precipitation.
As this concern, crystallization method described here may cause forming the fluazinam of one or more New Polycrystalline shape thing forms, or its mixture.Thus, on the other hand, the present invention points to the fluazinam of New Polycrystalline shape thing form substantially, referred to herein as " polymorph form I " and " polymorph form II ", and the mixture of described polymorph.The present invention also provides for the preparation of this New Polycrystalline shape thing and the method that contains the medicinal compositions of this polymorph, and uses it for the method for resisting the biology that agricultural and gardening farm crop are harmful to.
Solid exists with the form of amorphous or crystallization.In the situation of crystallized form, molecule is arranged with the form of three-dimensional lattice.When compound from solution or slurries during recrystallization, it may be with the crystallization of arranging of different space lattices, this character is called as " polymorph ", each different crystalline form is called as " polymorph ".The different polymorph form of known substance can differ from one another in one or more physicalies, for example solvability and dissociating property, true density, crystal shape, compacting behavior, flowability, and/or solid-state stability.When chemical substance exists with two kinds of (or more kinds of) polymorph forms, pass through at a certain temperature sufficiently long after the time, unsettled form can change into form more stable on thermokinetics usually.When this conversion was unhappy, unsettled form was called as " metastable state " form on thermokinetics.Generally speaking, stable form has the highest fusing point, minimum solvability and maximum chemical stability.Yet under normal storage requirement, thereby the metastable state form can have enough chemistry and physical stability can be used with commercial form.And although the metastable state form is so unstable, it may have than the more welcome performance of stable form, better modeling ability for example, improved water dispersible etc.
For fluazinam, there is not known crystallized form to exist.The present inventor through after a large amount of tests, has found the fluazinam of two kinds of new crystallized forms, is referred to as form I and form II.These two kinds of forms have different spectral response curves, and as they remarkable different means of differential scanning calorimetry (DSC) graphic representations, X-ray diffractogram and infrared (IR) spectrogram are shown.
Form I
In one embodiment, the invention provides the 3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl) of new crystallization polymorph form-α, α, α-three fluoro-2,6-dinitrobenzene-para-totuidine (fluazinam) is called as " form I ".This new, astonishing polymorph is characterised in that, DSC for example, X-ray powder diffraction pattern and/or infrared spectrum.
For example, as shown in Figure 1, form I has X-ray powder diffraction figure, and it has the characteristic peak (with angle 2 θ (+/-0.2 ° of θ) expression) in following one or more positions: 8.7,10,12.0,13.7,14.5,17.4,18.5,19.7,21.8,22.9 and 30.2.This X-ray powder diffraction is operation collection under 40kV and 30mA on Philips powder diffractometer PW1050/70, and (wavelength equals to use CuK α radiation
) and diffraction light graphite monochromator.Typical θ-2 θ sweep limit is 3-35 ° of 2 θ, and the stepping yardstick is 0.05 °, and the timing in per step is 0.5 second.
Use agate alms bowl and pestle that sample is ground.Then the powder that obtains is pressed in the cavity of the 20mm*15mm of aluminum specimen holder and dark 0.5mm.
And, (only shown 3000cm such as Fig. 2
-1Scope) shown in, form I also has at 3390cm
-1Near have infrared (IR) spectrogram of characteristic peak, be fourier-transform infrared (FT-IR) the spectrograph ReactIR that uses Mettler ToledoAutochem (ATR method, MCT detector)
TM1000, diamond-shaped windows, DuraSample1IR
TMSampler is measured.The rhombus sensor has the ZnSe optical focus of standard.Powdered sample is compressed and with 4cm in sample preparation device
-1Resolution carry out 256 times scanning.
And as shown in Figure 3, form I also has means of differential scanning calorimetry (DSC) graphic representation, and Mettler Toledo's have 821 when adopting
eDuring the dsc measurement of module, it is characterized in that near about 115.5 ℃, occurring main endotherm(ic)peak.In with the measuring process of carrying out under 10 ℃ of 2 scanning speed and/or the per minutes, the sample after weighing (2-4mg) is cleaned with nitrogen gas stream.Use the aluminum standard crucible of 40 μ L.Use STAR
eSoftware is finished assessment." about 115.5 ℃ " refer to from 114 ℃ to 117 ℃ as used herein.Consider thus, be to be understood that the heat absorption of measuring by a specific differential scanning calorimeter depends on a plurality of factors, comprise heating rate (being scanning speed), the calibration standard of use rectifies an instrument, relative humidity, and the chemical purity of specimen.Thus, the heat absorption of the DSC apparatus measures by afore mentioned rules may change reach ± 1.5 ℃ more than.
Form I is usually with the form crystallization of prism, and typical large yellow as described herein is prismatic.
On the other hand, the invention provides the method for the new fluazinam polymorph form I of preparation.Form I can prepare like this, and fluazinam is dissolved in an amount of solvent or solvent mixture, and heating makes its dissolving, and then cooling is settled out product.Selectively, fluazinam is dissolved in the soluble solvent of fluazinam, and adds the insoluble or sl. sol. solvent of this compound of the second (anti-solvent), until precipitation occurs.As well known in the prior art, the crystal seed that reaction can also type of service I as seed with induced precipitation.
Fluazinam original material for the preparation of form I can be any type of fluazinam, comprise according to US Patent No. 4,331, the fluazinam of 670 preparations, amorphous fluazinam, form II fluazinam, the mixture of form I and form II fluazinam, or arbitrarily other fluazinam well known in the prior art.
For example, in one embodiment, form I can prepare like this, from being selected from ethanol, and acetonitrile, crystallization fluazinam in the solvent of methylene dichloride and normal hexane, and separate the crystallization that obtains.A kind of preferred embodiment in, the method comprises the preparation solution of fluazinam in one or more aforementioned solvents, preferably by heating until dissolve complete, then cooling solution is until crystallization occurs.Usually, enough at the lower cooling solution of room temperature (being defined as about 20 ℃ to about 25 ℃ at this), yet, solution can be cooled to lower temperature, for example 0 ℃, 5 ℃, 10 ℃, 15 ℃ etc.Then can come fractional crystallization by any easily method well known in the prior art, for example filter, centrifugal etc.
Form I can also prepare by crystallization fluazinam from ether, and fluazinam is dissolved in the ether, preferably at room temperature, and flask partly open wide is placed so that solvent slowly volatilizees.Little by little, begin to occur crystallization, usually occur with large yellow prismatic form, then be isolated in a conventional manner.In general, the solvent evaporates of some only before crystallization begins to occur for example accounts for the about 10-90% that evaporate into airborne solvent, causes the appearance of form I crystallization.
Form II
In another embodiment, the invention provides the 3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl) of new crystallization polymorph form-α, α, α-three fluoro-2,6-dinitrobenzene-para-totuidine (fluazinam) is called as " form II ".This new, astonishing polymorph is characterised in that, DSC for example, X-ray powder diffraction pattern and/or infrared spectrum.
For example, as shown in Figure 4, form II has X-ray powder diffraction figure, and it has the characteristic peak (with angle 2 θ (+/-0.2 ° of θ) expression) in following one or more positions: 7.4,10.4,13.4,15.1,18.95,20,20.4,21.05,21.3,22.2,24.9,27.15,28.6 and 30.5.This X-ray powder diffraction is as indicated above the measurement.
And, (only shown 3000cm such as Fig. 5
-1Scope) shown in, form II also has at about 3375cm
-1Near have infrared (IR) spectrogram of characteristic peak, be to use fourier-transform infrared (FT-IR) spectrometer measurement as indicated above.
And as shown in Figure 6, form II also has means of differential scanning calorimetry (DSC) graphic representation, when adopting the simple regression system, it is characterized in that occurring main endotherm(ic)peak near about 109 ℃ (form II becomes liquid).Curve further shown by transform to form I that crystallization causes in about 115.5 ℃ heat absorption.This curve is to use differential scanning calorimeter as indicated above to measure." about 109 ℃ " refer to from about 107.5 ℃ to about 110.5 ℃ as used herein.
Form II is typically bright yellow spicule usually with the form crystallization of spicule.
On the other hand, the invention provides the method for the new fluazinam polymorph form II of preparation.Form II can prepare like this, and fluazinam is dissolved in an amount of solvent or solvent mixture, and heating makes its dissolving, and then cooling is settled out product.Selectively, fluazinam is dissolved in the soluble solvent, and adds the insoluble or sl. sol. solvent of compound (anti-solvent) of the second, until precipitation occurs.As well known in the prior art, the crystal seed that reaction can also type of service II as seed with induced precipitation.
Fluazinam original material for the preparation of form II can be any type of fluazinam, comprise according to US Patent No. 4,331, the fluazinam of 670 preparations, amorphous fluazinam, form I fluazinam, the mixture of form I and form II fluazinam, or arbitrarily other fluazinam well known in the prior art.
For example, form II can also prepare by crystallization fluazinam from ether, fluazinam is dissolved in the ether, preferably at room temperature, and rapid solvent flashing.This causes the formation of crystallization, usually with the form of bright yellow spicule, then is isolated in a conventional manner.
Form II also can prepare by the ethanolic soln of preparation fluazinam; Mode with preparation form I as indicated above prepares the solution of fluazinam in ethanol.Yet be not to be settled out product by cooling, but solution is exposed in the environment, so that partial solvent slowly volatilizees.Little by little, begin to occur crystallization, the form with bright yellow spicule occurs usually, then is isolated.In general, the solvent evaporates of some only before crystallization begins to occur for example accounts for the about 10-90% that evaporate into airborne solvent, causes the appearance of form II crystallization.
The mixture of form I and form II
In another embodiment, the invention provides 3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)-α, α, α-three fluoro-2, the polymorph form I of 6-dinitrobenzene-para-totuidine (fluazinam) and the mixture of form II.
This mixture has roughly X-ray powder diffraction figure as shown in Figure 7.And this mixture also has roughly and (has only shown 3000cm such as Fig. 8
-1Scope) shown in infrared spectrum.And this mixture also has roughly differential DSC heat scan graphic representation as shown in Figure 9, is to use differential scanning calorimeter as indicated above to measure.
Fluazinam original material for the preparation of the mixture of form I and form II can be any type of fluazinam, comprise according to US Patent No. 4,331, the fluazinam of 670 preparations, amorphous fluazinam, form I fluazinam, form II fluazinam, or arbitrarily other fluazinam well known in the prior art.
The mixture of form I and form II can be simply mixes to obtain mixture by the polymorph with the polymorph of form I and form II and prepares.Yet, also can be by from being selected from Virahol, crystallization goes out fluazinam in the solvent of normal hexane and toluene, and separates the crystallization that obtains and prepare this mixture.A kind of preferred embodiment in, the method comprises the preparation solution of fluazinam in one or more above-mentioned solvents, preferably by heating until dissolve complete, cooling solution is until crystallization occurs, and separates this crystallization.Usually, it is enough that solution is cooled to room temperature, yet, solution can be cooled to lower temperature, for example 0 ℃, 5 ℃, 10 ℃, 15 ℃ etc.
The mixture of form I and form II also can add anti-solvent by fluazinam being dissolved in the soluble solvent of described compound, separates the crystallization that obtains.A kind of preferred embodiment in, solvent is acetone.In another preferred embodiment, anti-solvent is water.
Composition and application
People have understood fluazinam and have resisted harmful biology such as insect, acarid, the biological aspect of fungus and bacterium and so on has outstanding performance, for example its outstanding antimycotic and anti-bacterial effect is used for the Industrial products that the harmful fungus and bacterium of control is being stored, breeding on seed and the fruit is such as aspergillus tubigensis (Aspergillus sp.), gibberella (Gibberella sp.) and Penicillium notatum (Penicilliumsp.).
Fluazinam also is being very effective aspect the growth of control harmful organism on agricultural and gardening farm crop and upland plant, for example resemble lepidopterous small cabbage moth (Plutella Xylostella), wild cabbage moths attracted by lamplight (Mamestra brassicae) and prodenia litura (Spodoptera litura); Resemble rice green leafhopper (Nephotettix cincticeps) and the small brown rice planthopper (Delphacodesstriatella) of Hemiptera; Resemble Callosobruchus chimensis and the ladybug of eggplant 28 stars (Epilachna vigintioctopunctata) of Coleoptera; Resemble dipterous housefly (Musca domestica) and Culexopipiens pallens; Resemble the mite class of Tetranychus urticae (Tetranychus urticae) and cotton spider mites (Tetranychus telarius) and panonychus citri (Panonychus citri); Resemble Pyricularia oryzae (Pyricularia oryzae), dry thread Pyrenomycetes (Rhizoctonia solani), the former bacterium of cucumber anthracnose (Collectotrichum lagenarium), Pseudopernospora cubensis, melon powdery mildew (Sphaerotheca fuliginea), phytophthora infestans (Phytophthorainfestans), base shell bacterium between citrus (Diaporthe citri), Alternaria solani (Alternariasolani), apple black star bacteria (Venturia inaequalis), Plasmopara viticola (Plasmoparaviticola), the pathogen of Botrytis cinerea (otrytis cinerea), the fungus and bacterium on plant of puccinia triticinia (Puccinia recondita) and sclerotinite (Sclerotinia sclerotiorum).
Also has outstanding performance aspect the fungi that fluazinam particularly is harmful to agricultural and gardening plant at the various harmful biologies of control.
Thus, in one embodiment, the present invention also provides the composition that contains this new crystallization polymorph to be used for control and has resisted the growth of harmful organism on agricultural and gardening farm crop and upland plant, insect for example, acarid, fungus and bacterium.In one embodiment, said composition comprises the crystallization polymorph of the form I of fluazinam; And acceptable auxiliary.In another embodiment, said composition comprises crystallization polymorph and the acceptable auxiliary of the form II of fluazinam.In another embodiment, said composition comprises the mixture of the crystallization polymorph of the form I of fluazinam and form II; And acceptable auxiliary.
The present invention also provides and has resisted insect, acarid, and the method for fungus and bacterium comprises to insect, acarid, fungus and bacterium impose the composition of the present invention of effective dose.
The invention still further relates to the method for protection farm crop and upland plant, comprise protection Industrial products therefrom, for example seed and fruit are by impose the composition of the present invention of effective dose to farm crop or product.
The concentration of the fluazinam polymorph that uses in composition of the present invention depends on the harmful organism as target, application method, and the dosage of the form of composition and activeconstituents.Concentration is not crucial, and its scope is usually from about 1 to 10,000ppm, preferably from about 20 to 2,000ppm.
Composition can prepare with various forms, dust for example, wettable powder, emulsifiable concentrate, the inertia emulsion, oil solution, aerosol etc., with auxiliary as agricultural composition.Said composition can be diluted to suitable concentration use or not dilute use.
Applicable auxiliary comprises for example talcum of powder carrier, kaolin, wilkinite, diatomite, silicon-dioxide, clay and starch; Liquid diluent is water for example, dimethylbenzene, toluene, dimethyl sulfoxide (DMSO), dimethyl formamide, acetonitrile, and ethanol; Emulsifying dispersant, tensio-active agent is sodium alkyl benzene sulfonate for example, polyoxyethylene alkylaryl ether, sodium naphthalene sulfonate formaldehyde enriched material, ether calcium sulfate, Volpo S 10 dodecyl phenylate, polyoxyethylene ten diether, polyoxyethylene fatty acid ester, sodium alkyl sulfate, the vitriol of polyoxyethylene alkylaryl ether and dialkyl group amber sulfonate etc.
Miticide, the activity component concentration in mycocide or the bactericide composition are 5-80wt.% under the state of oiliness enriched material usually, are 0.5-30wt.% under the state of dust, are 5-60wt.% under the state of wettable powder.Also may be in conjunction with other agricultural additive other sterilant for example, miticide, and/or plant-growth regulator.Sometimes find to have synergy.Other agricultural additive comprises organophosphorus ester compound, the carbaminate compounds, dithio (or sulfo-) carbaminate compounds, the organochlorine compounds, the dinitrobenzene compounds, organosulfur or organo-metallic compounds, antibiotic compound, the diphenyl ether compound of replacement, carbamide compounds, compound in triazine class, benzoyl urea compound, pyrethroid coumpound, imine compound and benzimidazoles compound and more specifically, process for preparation of benzoylurea compounds is N-(2,6-difluoro benzoyl)-N '-(to chlorobenzene) urea for example; Pyrethroid insecticides is alpha-cyano-3-phenoxy benzyl-2-(4-chlorobenzene) isopentanoate for example; The imines series bactericidal agent is N-(3,5-dichlorobenzene)-1 for example, 2-dimethylcyclopropane-1,2-dicarboxyl imide; Benzimidazole germicide is methyl isophthalic acid-(butyl formamyl)-2-carboxylamine benzoglyoxaline for example; The thiocarbamate series bactericidal agent is S-ethyl n-(the 3-dimethyl propyl is amino) thiocarbamate hydrochlorate for example.The dithiocarbamic acid series bactericidal agent is vinyl bisdithiocarbamic manganese for example; The ureas sterilant is 2-cyano group-N-(ethyl carbonyl amino)-2-(methoxyl group is amino) ethanamide for example.
Following embodiment is be used to illustrating in greater detail the specific embodiment of the present invention.But it can be interpreted as the restriction to broad range of the present invention.Those skilled in the art can easily carry out various changes and modifications and can not exceed the spirit and scope of the present invention fundamental principle disclosed herein.
Experimental section:
Use following abbreviation at this:
The ACP-2-amido-3-5-trifluoro picoline
The CAN-acetonitrile
CNB-2,4 ,-two chloro-3,5-dinitro-p-trifluorotoluene
The DMF-dimethyl formamide
The DMSO-methyl-sulphoxide
EtOH-ethanol
The MEK-methylethylketone
The MIBK-methyl iso-butyl ketone (MIBK)
The THF-tetrahydrofuran (THF)
Embodiment 1-solvent effect
Shown in the following scheme, by in several organic solvents, compound 1A and 2A coupling being prepared fluazinam.To be dissolved in (1) of 1.5 grams in the organic solvent of 10ml, the KOH-3 equivalent of (2) of 2.5 grams-excessive 5%, 1.5 gram is introduced in the round-bottomed flask with magnetic agitation of 25ml.Mixture takes out sample until reaction terminating continuously 30 ℃ of lower stirrings also.
Table 2 has represented all kinds of SOLVENTS impact synthetic on fluazinam under pure and azeotrope form.
Table 2: the impact of all kinds of SOLVENTS under pure and azeotrope form
| Solvent | (%) impurity a | (％)4 b | (％)1A c | (％)2A d | (％)3 |
| Acetonitrile | 3.7％ | 6.5％ | 3.1％ | 0.0％ | 86.7％ |
| Acetonitrile-84% | 4.6％ | 15.8％ | 2.5％ | 8.1％ | 69.0％ |
| THF | 2.8％ | 7.2％ | 2.5％ | 0.0％ | 87.5％ |
| THF-95％ | 1.9％ | 8.0％ | 2.8％ | 2.0％ | 85.3％ |
| MIBK | 3.8％ | 1.2％ | 2.0％ | 1.0％ | 92.0％ |
| MIBK-98％ | 2.2％ | 1.8％ | 2.8％ | 1.1％ | 92.1％ |
| MEK | 8.1％ | 3.3％ | 2.4％ | 3.6％ | 82.6％ |
| MEK-88％ | 5.3％ | 9.0％ | 2.5％ | 10.3％ | 72.9％ |
| DMF | 16.7％ | 8.5％ | 2.3％ | 3.6％ | 68.9％ |
| DMSO | 8.6％ | 14.1％ | 11.1％ | 2.0％ | 64.2％ |
Total impurity of confirming in the a=reaction is outside the removal of impurity 4.
The per-cent of b=hydrolysising by-product 4.
The unreacted reactant 1A of c=.
The unreacted reactant 2A of d=.
The result shows:
1.MIBK no matter be that productive rate or purity all surmount other solvent in the pure performance with under the wet form.
2.MIBK be that unique azeotrope performance does not subtract in the solvent of its neat solvent performance.
3. the whole solvents except MIBK all show the higher trend that is tending towards forming hydrolysate 4 under the azeotrope form.
4.DMF show the impurity of unusual high level with DMSO, and be not suitable for thus the method.
Embodiment 2-synthesis step (0.3mol scale)
Raw material 1A, CNB, and 2A, ACP, synthetic by following manner:
Raw material 1A
Synthesizing of fluazinam
Order adds following reactant in the three neck oil ring reactors that thermometer and condenser are housed: 60 gram ACP (=0.3mol), 95 gram CNB powder (excessive 3%mol) and 340 restrain MIBK azeotropes (containing 1.6% water) and also are cooled to 20-25 ℃.
Be still at low temperatures, the KOH (=3.5mol equivalent) of 70 grams are sequentially added by per 20 minutes 10 grams, prevent simultaneously that temperature is elevated to and be higher than 30 ℃.Further stirring the mixture after the interpolation (under room temperature 25-30 ℃) until wherein there is not the further consumption (measuring by HPLC) of reactant.
Make the mixture acidifying and restrain 5% sodium chloride solution purging compound with 400 by adding 400 grams, 5% hydrochloric acid.After the water layer of this two-phase mixture is by acidifying, with funnel organic phase is separated and then to be made solvent under vacuum, evaporate into drying.
The raw product that obtains is the yellow fluazinam products of about 150 grams, and purity is about 95%, and chemical yield is about 98%.
Crystallization is to obtain the yellow powder shape product of about 140 grams in hot ethanol with raw product, and its purity is higher than 98%, and overall yield is 90%.
The preparation of embodiment 3-form I fluazinam
2 gram fluazinam are heated until fully dissolving in 10 gram ethanol.Then solution is cooled to room temperature.Filter out yellow crystal and drying in 40 ℃ baking oven.This crystallization is form I fluazinam.
The preparation of embodiment 4-form I fluazinam
The fluazinam of 15 grams and the acetonitrile of 10 grams are heated until fully dissolving.Then be cooled to room temperature.Filter out yellow crystal and 40 ℃ of dryings.This crystallization is form I fluazinam.
The preparation of embodiment 5-form I fluazinam
Be dissolved in the methylene dichloride of 10 grams by the fluazinam of low-grade fever on hot-plate with 2 grams.Hot solution is stirred until obtain crystallization at hot-plate.Filter out yellow crystal and 40 ℃ of dryings.This crystallization is form I fluazinam.
The preparation of embodiment 6-form I fluazinam
The fluazinam of 2 grams and the normal hexane of 30 grams are heated until fully dissolving.Then cooling solution is to room temperature, filters out crystallization and 40 ℃ of dryings.This crystallization is form I fluazinam.
The preparation of embodiment 7-form I fluazinam
The fluazinam of 2 grams at room temperature is dissolved in the ether of 10 grams.Slowly solvent flashing (flask is placed under the room temperature partly unlimitedly) is so that large yellow prismatic the appearance.Filter out crystallization and 40 ℃ of dryings.This crystallization is form I fluazinam.
The preparation of embodiment 8-form II fluazinam
According to described in the embodiment 52 fluazinam that restrain being dissolved in the ether of 10 grams.Solvent is volatilized from flask fast and bright yellow spicule crystallization occurs.From flask, collect this crystallization and 40 ℃ of dryings.This crystallization is form II fluazinam.
The preparation of embodiment 9-form II fluazinam
According to described in the embodiment 1 with the fluazinam heating for dissolving of 2 grams in the ethanol of 10 grams, except the uncovered placement of flask and part ethanol volatilize from solution.Crystallization is faster and occur bright yellow spicule at the bottom of flask.Filter this crystallization and 40 ℃ of dryings.This crystallization is form II fluazinam.
The preparation of the mixture of embodiment 10-form I and form II fluazinam
The fluazinam of 3 grams and the Virahol of 10 grams are heated until fully dissolving.Solution is slowly cooled to room temperature.Filter yellow crystal and 40 ℃ of dryings.This crystallization is the mixture of form I and form II fluazinam.
The preparation of the mixture of embodiment 11-form I and form II fluazinam
The fluazinam of 6 grams and the toluene of 6 grams are heated until fully dissolving.Solution is cooled to 0 ℃ by ice-water bath.Filtering for crystallizing and 40 ℃ of dryings.This crystallization is the mixture of form I and form II fluazinam.
The preparation of the mixture of embodiment 12-form I and form II fluazinam
The fluazinam of 10 grams at room temperature is dissolved in the acetone of 10 grams.Add several dripping as anti-solvent.Crystallization occurs at once.Filtering for crystallizing and 40 ℃ of dryings.This crystallization is the mixture of form I and form II fluazinam.
Although specific embodiment of the present invention is introduced and illustrates that the present invention is not limited to embodiment described here.Various modification change, and change, and substituting and replacing all is apparent for a person skilled in the art, can't deviate from spirit and scope of the present invention.
Claims (15)
1.3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)-α, α, α-three fluoro-2, the crystallization polymorph form I of 6-dinitrobenzene-para-totuidine (fluazinam), wherein the characteristic peak that has of the X-ray powder diffraction figure of this polymorph is illustrated in approximately 8.7,10,12.0,13.7,14.5,17.4,18.5,19.7,21.8,22.9 and 30.2 with angle 2 θ (+/-0.20 ° of θ), and wherein the X-ray powder diffraction figure of polymorph basically as shown in Figure 1.
2. crystallization polymorph as claimed in claim 1, wherein infrared (IR) spectrogram of polymorph is at about 3390cm
-1Has characteristic peak.
3. crystallization polymorph as claimed in claim 1, wherein polymorph at 3000cm
-1Infrared (IR) spectrogram of scope basically as shown in Figure 2.
4. crystallization polymorph as claimed in claim 1, wherein polymorph is when adopting differential scanning calorimeter (DSC) to measure with the scanning speed of 10 ℃ of per minutes, and it a single main endotherm(ic)peak occurs at about 115.5 ℃.
5. crystallization polymorph as claimed in claim 1, wherein the means of differential scanning calorimetry of polymorph (DSC) graphic representation basically as shown in Figure 3.
6. crystallization polymorph as claimed in claim 1 is in prismatic form.
7. the method for preparing crystallization polymorph form I claimed in claim 1, the method comprise the step of the crystallization that the described compound of crystallization and separation obtain from solvent, and wherein said solvent is selected from acetonitrile, methylene dichloride, and normal hexane.
8. method as claimed in claim 7 may further comprise the steps:
I. prepare 3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)-α, α, α-three fluoro-2, the solution of 6-dinitrobenzene-para-totuidine in solvent, wherein said solvent is selected from acetonitrile,
Methylene dichloride, and normal hexane;
Ii. cool off this solution so that form the crystallization of described compound; With
Iii. separate this crystallization.
9. prepare the method for crystallization polymorph form I claimed in claim 1, the method may further comprise the steps:
I. prepare 3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)-α, α, α-three fluoro-2, the solution of 6-dinitrobenzene-para-totuidine in solvent, wherein said solvent is selected from ethanol;
Ii. cool off this solution so that form the crystallization of described compound; With
Iii. separate this crystallization.
10. such as claim 7 or 9 described methods, wherein step is to be undertaken by heating a), and the solution that wherein step a) is obtained is cooled to room temperature.
11. prepare the method for crystallization polymorph form I claimed in claim 1, the method comprises the solution of the described compound of preparation in ether; Slow solvent flashing; The step of then separating the crystallization that obtains.
12. method as claimed in claim 11 is wherein come solvent flashing by solution is exposed to environment.
13. one kind is used for resisting insect, acarid, the composition of fungus and bacterium, it contains just like each described 3-chloro-N-of claim 1-6 (3-chloro-5-trifluoromethyl-2-pyridyl)-α, α, α-three fluoro-2, the crystallization polymorph form I of 6-dinitrobenzene-para-totuidine; And acceptable auxiliary.
14. one kind is used for resisting insect, acarid, and the method for fungus and bacterium comprises to insect, acarid, fungi or bacterium impose the composition as claimed in claim 13 of effective dose.
15. avoid being selected from insect for the protection of farm crop for one kind, acarid, the method for the harmful organism infringement of fungus and bacterium comprises the composition as claimed in claim 13 that imposes effective dose to farm crop.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL172137 | 2005-11-23 | ||
| IL172137A IL172137A0 (en) | 2005-11-23 | 2005-11-23 | Process for prep aring pyridinamines |
| IL172685A IL172685A0 (en) | 2005-12-19 | 2005-12-19 | Polymorphs of 3-chloro-n-(3-chloro-5-trifluoromethyl-2- pyridyl)-??,??,??-trifluoro-2,6-dinitro-p-toluidine |
| IL172685 | 2005-12-19 | ||
| PCT/IL2006/001351 WO2007060662A2 (en) | 2005-11-23 | 2006-11-23 | Process for preparing pyridinamines and novel polymorphs thereof |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2012104996506A Division CN102977011A (en) | 2005-11-23 | 2006-11-23 | Process for preparing pyridinamines and novel polymorphs thereof |
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| CN101534644A CN101534644A (en) | 2009-09-16 |
| CN101534644B true CN101534644B (en) | 2013-01-16 |
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| CN200680043978.XA Expired - Fee Related CN101534644B (en) | 2005-11-23 | 2006-11-23 | Process for preparing pyridinamines and novel polymorphs thereof |
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| Country | Link |
|---|---|
| CN (1) | CN101534644B (en) |
| IL (1) | IL172137A0 (en) |
| ZA (1) | ZA200805360B (en) |
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| US11632954B2 (en) * | 2017-07-17 | 2023-04-25 | Adama Makhteshim Ltd. | Polymorphs of 5-fluoro-4-imino-3-methyl-1 -tosyl-3,4-dihydropyrimidin-2-one |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4331670A (en) * | 1979-12-25 | 1982-05-25 | Ishihara Sangyo Kaisha, Ltd. | Pyridylanilines |
| US5081133A (en) * | 1989-02-21 | 1992-01-14 | Basf Aktiengesellschaft | 2-anilinocyanopyridines having fungicidal properties |
-
2005
- 2005-11-23 IL IL172137A patent/IL172137A0/en unknown
-
2006
- 2006-11-23 CN CN200680043978.XA patent/CN101534644B/en not_active Expired - Fee Related
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2008
- 2008-06-19 ZA ZA200805360A patent/ZA200805360B/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4331670A (en) * | 1979-12-25 | 1982-05-25 | Ishihara Sangyo Kaisha, Ltd. | Pyridylanilines |
| US5081133A (en) * | 1989-02-21 | 1992-01-14 | Basf Aktiengesellschaft | 2-anilinocyanopyridines having fungicidal properties |
Non-Patent Citations (2)
| Title |
|---|
| Mino R. Caira.Crystalline Polymorphism of Organic Compounds..《Topics in Current Chemistry》.1998,第198卷163-208. * |
| 主编:胡笑形.fluazinam.《新英汉农药辞典(上)》.外文出版社,1999,579. * |
Also Published As
| Publication number | Publication date |
|---|---|
| IL172137A0 (en) | 2006-04-10 |
| ZA200805360B (en) | 2009-11-25 |
| CN101534644A (en) | 2009-09-16 |
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