CN108368047B - Picoxystrobin crystal form, preparation method and application thereof - Google Patents
Picoxystrobin crystal form, preparation method and application thereof Download PDFInfo
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- CN108368047B CN108368047B CN201780004342.2A CN201780004342A CN108368047B CN 108368047 B CN108368047 B CN 108368047B CN 201780004342 A CN201780004342 A CN 201780004342A CN 108368047 B CN108368047 B CN 108368047B
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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Abstract
Novel crystalline forms of the compound of formula (I) (picoxystrobin) are provided. The novel crystal form of picoxystrobin can be prepared by crystallization from a solution in a suitable solvent. Fungicidal compositions comprising the novel crystalline forms, methods for controlling fungal infestation at a locus and uses of the novel crystalline forms are also provided.
Description
Cross Reference to Related Applications
This application claims priority to uk patent application GB1600977.1 filed on 2016, 1, 19, the contents of which are incorporated herein by reference in their entirety.
Technical Field
The present invention relates to a novel crystal form of picoxystrobin (picoxystrobin). The invention further relates to a process for preparing the novel crystalline form. Further, the invention relates to the use of the new crystalline form.
Picoxystrobin (chemical name is (E) -3-methoxy-2- [2- (6-trifluoromethyl-2-pyridyloxymethyl) phenyl ] methyl acrylate) has the following structural formula (I):
picoxystrobin belongs to the strobilurin (strobilurin) class of chemicals which are used as fungicides, in particular for controlling a range of fungal diseases including brown rust, brown spot, powdery mildew and net blotch in cereals, pulses and oilseeds. Picoxystrobin is a prophylactic and therapeutic fungicide with systemic transmembrane movement that acts by blocking electron transfer at the Qo center of cytochrome Bc1 to inhibit mitochondrial respiration.
Commercially available picoxystrobin products are generally manufactured by processes as described in EP 0278595, US 6,015,905, CN 102115458A, CN 103030598a and CN 103626691 a.
For example, US 6,015,905 discloses a process for preparing picoxystrobin starting from methyl-2- (o-tolyl) acetate according to the reaction scheme shown in scheme 1 below.
Picoxystrobin prepared by these methods described above is amorphous and difficult to formulate. In particular, the product has a high tendency to aggregate, especially after long-term storage.
Accordingly, there is a need in the art for new forms of picoxystrobin which exhibit improved properties (e.g. improved storage stability).
Disclosure of Invention
A new crystalline variant of picoxystrobin has now been found which is easy to formulate into agrochemical compositions and which shows a high degree of stability upon formulation. In particular, this crystal modification (hereinafter referred to as 'crystal modification I') shows a very low tendency to aggregate when formulated.
Accordingly, in a first aspect, the present invention provides picoxystrobin crystal modification I exhibiting at least 4 of the following reflections as 2 θ values in an X-ray powder diffraction pattern recorded with Cu-K α radiation at 25 ℃:
2θ＝8.4613±0.2 (1)
2θ＝12.0227±0.2 (2)
2θ＝12.7030±0.2 (3)
2θ＝13.8834±0.2 (4)
2θ＝14.5237±0.2 (5)
2θ＝16.2243±0.2 (6)
2θ＝16.3844±0.2 (7)
2θ＝17.1247±0.2 (8)
2θ＝17.6249±0.2 (9)
2θ＝18.7653±0.2 (10)
2θ＝20.3659±0.2 (11)
2θ＝21.2663±0.2 (12)
2θ＝22.0466±0.2 (13)
2θ＝22.1466±0.2 (14)
2θ＝22.9469±0.2 (15)
2θ＝23.7272±0.2 (16)
2θ＝24.1474±0.2 (17)
2θ＝25.3278±0.2 (18)
2θ＝25.6479±0.2 (19)
2θ＝26.1681±0.2 (20)
2θ＝26.7884±0.2 (21)
2θ＝28.3890±0.2 (22)
2θ＝31.0300±0.2 (23)
2θ＝35.4117±0.2 (24)
As mentioned above, picoxystrobin crystal modification I shows at least 4 of the reflections listed above in its X-ray powder diffraction pattern. More preferably, the crystalline modification I exhibits at least 5, at least 7 of the above reflections.
More preferably, the picoxystrobin crystal modification I has an X-ray powder diffraction pattern showing at least 4, more preferably at least 5, still more preferably at least 7, still more preferably all of the following reflections:
2θ＝8.4613±0.2 (1)
2θ＝12.7030±0.2 (3)
2θ＝13.8834±0.2 (4)
2θ＝16.3844±0.2 (7)
2θ＝17.6249±0.2 (9)
2θ＝21.2663±0.2 (12)
2θ＝22.9469±0.2 (15)
2θ＝25.3278±0.2 (18)
in a preferred embodiment picoxystrobin crystal modification I exhibits all the above reflections (1) to (24).
In a particularly preferred embodiment, picoxystrobin crystal modification I exhibits a powder X-ray diffraction pattern substantially the same as shown in figure 1.
Furthermore, picoxystrobin crystal modification I may be alternatively characterized, preferably further characterized by IR spectroscopy. At a scan number of 32 and a resolution of 4cm-1The IR spectroscopy was performed. The IR spectrum of picoxystrobin crystal modification I is shown in FIG. 2, and the characteristic bands are about 1704.95, 1629.04, 1577.46, 1352.22, 1258.08, 1201.97, 1124.12, 983.51 and 810.19 cm-1To (3).
Picoxystrobin crystal modification I according to the invention may alternatively be characterized, preferably further by Differential Scanning Calorimetry (DSC), the results of which are shown in figure 3. The endothermic peak at about 79.115 ℃ is shown in fig. 3 with an onset temperature of about 73.872 ℃. The term "about 79.115 ℃ as used herein means the range of 75 ℃ to 80 ℃. The term "about 73.872 ℃ as used herein means the range of 72 ℃ to 75 ℃.
A particularly preferred picoxystrobin crystal modification I is a crystal modification exhibiting an X-ray powder diffraction pattern as described above and one or both of the IR and DSC spectra described above.
A study of single crystals of picoxystrobin crystal modification I showed that the basic crystal structure was monoclinic and had space group P21And c, the ratio of the total weight to the total weight. The characteristic data of the crystal structure of picoxystrobin crystal modification I are shown in table 1 below:
table 1: crystallographic data of picoxystrobin crystal modification I
Wherein:
a, b, c ═ length of unit cell (unit cell) edge
Angle of unit cell
Z is the number of molecules in a unit cell
The crystal structure of picoxystrobin crystal modification I is shown in fig. 4.
Picoxystrobin crystal modification I of the invention can be easily prepared by crystallizing the crystal modification from a solution of picoxystrobin in a solvent system. The solution may be prepared using picoxystrobin in any form, in particular amorphous picoxystrobin.
Accordingly, in another aspect, the present invention provides a method of forming picoxystrobin crystal modification I, the method comprising:
i) providing a picoxystrobin solution in a solvent system comprising one or more solvents;
ii) crystallizing the dissolved compound into picoxystrobin crystal modification I having formula I; and is
iii) separating the crystalline solid from the solvent system to produce picoxystrobin crystalline modification I.
As described above, the picoxystrobin solution may be formed by dissolving a suitable form of picoxystrobin in a solvent system. Amorphous picoxystrobin is one preferred starting material for forming the solution.
Generally, any suitable solvent may be used in the solvent system. Preferred solvents for use in the solvent system for the preparation of picoxystrobin crystal modification I are alcohols, in particular secondary and tertiary alcohols, optionally mixed with water; aliphatic or alicyclic alkanes, especially C5To C10Alkanes, more preferably C5To C7Alkanes, preferably substituted with one or more halogen moieties; substituted aromatic solvents, especially substituted benzenes, especially nitro-substituted and halogen-substituted aromatic compounds; an aromatic ether; ketones, especially lower alkyl ketones; nitriles, especially lower alkyl nitriles; and mixtures thereof.
'lower alkyl' refers to an alkyl moiety having from 1 to 4 carbon atoms.
Preferred halogen substituents are chloro moieties.
The use of primary alcohols, especially lower alcohols, especially methanol, and unsubstituted aromatic solvents, such as toluene, is preferably avoided.
Particularly preferred solvent systems for the preparation of picoxystrobin crystal modification I comprise isopropanol, tert-butanol, chloroform, dichloroethane, hexane, nitrobenzene, chlorobenzene, dichlorobenzene, trifluorotoluene, methyl ethyl ketone, acetonitrile or mixtures of one or more thereof. Preferred solvent mixtures include chloroform-hexane, THF-hexane, dichloromethane-hexane and THF-water.
In the present invention, picoxystrobin crystal modification I can be prepared by dissolving amorphous picoxystrobin in a solvent system comprising one solvent or a mixture of solvents. The amorphous starting material is dissolved in a solvent system to form a concentrated solution. Dissolution may be accomplished by heating the solvent system to a temperature from room or ambient temperature to the reflux temperature of the solution. Preferably, the solution is prepared at the reflux temperature of the solution. The concentration of picoxystrobin in the final solution depends on the solubility of picoxystrobin in the solvent system used.
The resulting homogeneous solution may then be cooled to a desired temperature, for example to room or ambient temperature or a temperature above room or ambient temperature, to crystallize the desired crystalline form from the solution. Alternatively, or in addition, the crystalline modification I can also be crystallized by concentrating the homogeneous solution at or below the reflux temperature of the solution, with or without vacuum.
In a preferred embodiment, the crystallization of crystalline modification I is aided by the addition of seeds of the desired crystalline form during the crystallization, which may facilitate or accelerate the crystallization process. The seed crystal is typically added in an amount ranging from 0.001% to 10% by weight, more preferably from 0.002% to 5%, still more preferably from 0.003% to 2.5%, still more preferably from 0.005% to 0.5% by weight, based on the weight of picoxystrobin present in the solution. The seed crystals are preferably added to the solution at a temperature below the boiling point of the solution.
Picoxystrobin crystal modification I was recovered by separating the crystallized material from the solvent system. Suitable techniques for this separation are known in the art and include filtration, centrifugation and decantation.
Thereafter, the isolated solid is preferably washed with a suitable solvent, which may be the same solvent system as used in step (i) for preparing the concentrated solution or a different solvent. Washing is typically carried out under cooling, for example between room temperature and 0 ℃, to reduce loss of crystalline product. The washing temperature depends on the solubility of the crystals in the solvent system used.
The picoxystrobin crystal modification I is particularly suitable for being prepared into a fungicidal composition.
Accordingly, in a further aspect, the present invention provides a fungicidal composition comprising picoxystrobin crystal modification I as described above.
The fungicidal composition may comprise picoxystrobin crystal modification I in any amount suitable to provide the desired activity. Preferred are compositions comprising less than 80% by weight, more preferably less than 50% by weight of picoxystrobin crystal modification I. Compositions comprising about 25% by weight picoxystrobin crystal modification I are preferred for many applications.
Picoxystrobin crystal modification I can be formulated in a known manner to provide a range of conventional formulations. Examples of such formulations include Suspensions (SC), oil-based suspensions (OD), Soluble Granules (SG), dispersible agents (DC), Emulsifiable Concentrates (EC), emulsion dressings, suspension dressings, Granules (GR), Microgranules (MG), Suspoemulsions (SE), and water dispersible granules (WG).
Picoxystrobin crystal modification I is particularly suitable as a formulation of a suspending agent (SC). In addition to the active compounds, suspending agents generally comprise surfactants, and also, if appropriate, one or more thickeners, antifreezes, biocides and any necessary auxiliaries.
Picoxystrobin crystal modification I may be present in the suspending agent (SC) composition at a concentration sufficient to achieve the dosages required in the art, for example from about 0.1% to about 50% by weight of the total mixture. The Suspension (SC) is generally prepared as follows: in picoxystrobin crystal modification I a solvent, in particular water, one or more dispersants or surfactants, and one or more further auxiliaries are incorporated.
Suitable dispersants are known in the art and are commercially available. Suitable dispersants include, but are not limited to, sodium, calcium and ammonium salts (optionally polyethoxylated) of lignosulfonic acid; sodium and ammonium salts of maleic anhydride copolymers; sodium salts of condensed phenolsulfonic acids; and naphthalene sulfonate-formaldehyde condensates. Lignosulfonates such as sodium lignosulfonate are particularly useful in the compositions of the present invention. Naphthalenesulfonate-formaldehyde condensates such as polymers of naphthalenesulfonic acid and formaldehyde and salts thereof (e.g., sodium salts) are also particularly useful in the compositions of the present invention.
Suitable thickeners for inclusion in the composition are known in the art and are commercially available. Suitable thickeners include, but are not limited to guar gum, pectin, casein, carrageenan, xanthan gum, alginates, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and carboxymethyl cellulose. Synthetic thickeners may be used and include derivatives of the above agents, as well as polyvinyl alcohol, polyacrylamide, polyvinyl pyrrolidone, various polyethers, copolymers thereof, and polyacrylic acid and salts thereof. Alkyl polyvinylpyrrolidones are particularly useful thickeners for the compositions of the present invention.
Suitable antifreeze agents for inclusion in the composition are known in the art and are commercially available. Suitable antifreeze agents include liquid polyols such as ethylene glycol, propylene glycol or glycerol. The antifreeze agent is generally present in an amount of from about 1 to about 20% by weight, especially from about 5 to about 10% by weight, based on the total weight of the composition.
One or more biocides or preservatives may also be included in the composition according to the invention. Suitable biocides are known in the art and include those based on isothiazolones, for example from the company Longsha (Lonza)
From Sol chemical company (Tho)Of r Chemie)
RS or from Rohm and Haas company&Haas) of
MK. Preservatives are typically present in the composition in an amount of from 0.05% to 0.5% by weight, based on the total weight of the composition.
The picoxystrobin crystal modification I may be the only active ingredient in the pesticide formulation or may be present in combination with one or more other active compounds including one or more insecticides, attractants, disinfectants, bactericides, acaricides, nematicides, fungicides, growth regulating substances, herbicides, safeners, fertilizers and semiochemicals.
Preferred active compounds for use in combination with the picoxystrobin crystal modification I are dexrazoxane (metaxyl), dodemorph (dodemorph), fenpropiram (fenpropimorph), fenpropidin (fenpropidin), biguanide salt (guazatine), spiroxamine (spiroxamine), triclopyr (tridemorph), pyrimethanil (pyrimethanil), cyprodinil (cypropidinyl), bidinonazole (bitertanol), bromocryptazole (bromobenzoxazole), ciclovir (cypropiconazole), dibenzazole (bifenoconazole), difenoconazole (difenoconazole), diniconazole (diniconazole), iprazole (epoxyconazole), fenpropizole (fenpropizole), trifloxystrobin (trifloxystrobin), propiconazole (trifloxystrobin (propiconazole), propiconazole (trifloxystrobin (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole (propi, Examples of the organic compound include, but are not limited to, meclizine (vinclozolin), maneb (maneb), mancozeb (mancozeb), ametram (metiram), deleam (thiram), beclomerid (boscalid), benezetil (carbazazim), jiaxin (carboxin), oxcarbazide (oxacarb), cyazofamid (cyazofamid), nitrothioquinone (dithianon), fenamidone (famoxadone), fenamidone (fenamidone), fenrimol (fenarimol), fudonil (flutoli), dinotefuran (quinoxyfen), methylpolyp (thiophanate-methyl), thiophanate (thionine-ethyl), fuberine (difenoxin), thifluanib (dinafunge), nitrofenofibrate (propathrin), thiflunil (propyrocarb), thiuram (propyrocarb) (propyrol), thiuram (propyrocarb), propyrocarb (propyrocarb) (propyrol), propyrocarb (propyrocarb) (propyrol), propyrocarb (propyrocarb) (propyrocarb), propyrol), propyrocarb (propyrocarb), propyrocarb (propyrocarb) (propyrocarb (propyrol), propyrocarb (propyrocarb) (propyrol), propyrocarb (propyrocarb) (propyrol), propyrocarb (propyrol), propyrocarb (propyrol), propcarb (propyrol), propyrocarb (propyrocarb) or propyrocarb (propyrol) (propyrocarb (propyrol), propyrocarb (propyrocarb) or (propcarb (propyrocarb) or propyrocarb (propyrol), propyrol) (propyrol), propyrocarb (propyrol) or (propyrocarb (propyrol), propyrol) (propyrocarb (propcarb (propyrol), propcarb (propyrol), propyrol) (propyrocarb, Cymoxanil (cycloxanil), fenhexamid (fenhexamid), fentin hydroxide (fendinacetate), fenoxanil (fenoxanil), fluazinam (fluazinam), fosetyl acid (foseyl), fosetyl-aluminium (foseyl-aluminium), propineb (iprovalicarb), fenaminone (metrafenone), troxamine (zoxamide), capsanthin (captan), fosfamide (folpet), dimethomorph (dimethorph), octopamine (azoxystrobin), dimoxystrobin (dimoxystrobin), fluoxastrobin (fluoxastrobin), kresoxim-methyl (kresoxim-methyl), metominostrobin (metominostrobin), orysastrobin (orysastrobin), prothromonazole (prothromonazole), thiopyrad (trifloxystrobin) or trifloxystrobin (trifloxystrobin).
Particularly preferred active ingredients for use in combination with picoxystrobin crystal modification I are ciclesonide, cetrapite, penconazole, tebuconazole, bensulide, prothioconazole, beclomethapyr and beclomethamine.
The composition of the present invention comprising picoxystrobin crystal modification I is active in controlling all undesired fungal pathogens that can be controlled using known picoxystrobin formulations. Fungal pathogens that may be controlled to cause fungal diseases include, for example:
alternaria species (Alternaria sp.) on vegetables, oilseed rape, sugar beet, soybean, cereals, cotton, fruits and rice (e.g. Alternaria solani (a. solani) or Alternaria (4.alternata)) on potatoes and other plants,
species of the genus serici (Aphanomyces sp.) on sugar beets and vegetables,
ascochyta sp on cotton and rice,
helminthosporium (Bipolaris) and helmholera spp (Drechslera spp.) on corn, cereals, rice and turf (e.g., helminthosporium coeruleum (d. teres) on barley, d. tritii-repentis on wheat),
powdery mildew (Blumeria graminis) on cereals,
botrytis cinerea (Botrytis cinerea) on strawberries, vegetables, flowers and vines (Botrytis cinerea),
Dolomyces sp (Botryodipliodia sp.) on cotton,
bremia lactucae (Bremia lactucae) on lettuce,
cercospora species (Cercospora sp.) on corn, soybean, rice and sugar beet (e.g., Cercospora saccharina (C. betula) on sugar beet),
coenospora (Cochliobolus) on corn, grain, rice (e.g., coenospora graminicola (Cochliobolus sativus) on grain, or coenospora gondii (Cochliobolus miyabenus) on rice));
corynebacterium species (Corynespora sp.) on soybeans, cotton, and other plants,
anthrax species (Colletotrichum sp.) on soybean, cotton, and other plants (e.g., Colletotrichum oxysporum (c. acutatum) on various plants),
curvularia sp on cereals and rice,
species of the genus Chrodiobyces (Diplodia sp.) on cereals and rice,
helminthosporium sp (Exserohilum sp.) on maize,
erysiphe cichororaceae (Erysiphe cichororaceae) and Sphaerotheca fuliginea (Sphaerotheca fuliginea) on cucumber plants,
fusarium (Fusarium) and Verticillium spp (e.g., Verticillium spp.) on various plants (e.g., Fusarium solani (v. dahliae)) (e.g., Fusarium graminearum (f. graminearum) on wheat),
Gaeumannomyces graminis on cereals,
gibberella sp (e.g., Gibberella fujikuroi) on cereals and rice,
gram staining complex on rice (grinstining complex),
helminthosporium sp on corn and rice (e.g., H. graminicola),
ascochyta species (macrophosmin sp.) on soybean and cotton,
species of the genus Michrodochium on plants, e.g., m.nivale on cereals,
mycosphaerella (mycosphaeraella) species on cereals, bananas and peanuts (e.g., Mycosphaerella graminicola (m.graminicola) on wheat, Mycosphaerella fijiensis (m.fijiensis) on bananas),
the genus P.fuscoporia (Phaeoisis) species on soybean,
phakopsora sp (e.g., phakopsora pachyrhizi (p. pachyrhizi) and phakopsora manillensis (Phakopsara meibomiae)) on plants,
phoma species (Phoma sp.) on soybean,
phomopsis sp on soybeans, sunflowers and grapevines (e.g., Phomopsis viticola on grapevines, Phomopsis helianthi on sunflowers (P.heliothis)),
Phytophthora infestans (Phytophthora infestans) on potatoes and tomatoes,
plasmopara viticola (Plasmopara viticola) on grapevine,
penicillium species (Penicilium sp.) on soybeans and cotton,
apple powdery mildew (Podosphaera leucotricha) on apples,
wheat-based rot fungi (Pseudocercospora herpotrichoides) on cereals,
pseudoperonospora sp (e.g., Pseudoperonospora cubensis on cucumber) on hop and cucumber plants,
puccinia sp (e.g., Puccinia sp) on cereals, corn and asparagus (e.g., Puccinia triticina and Puccinia striiformis on wheat (P.triticina), Asparagus rust (P.asparagi) on asparagus),
pyrenophora sp on cereals,
pyricularia oryzae (Pyricularia oryzae) on rice, Korea (Corticium sakii), Scopulariopsis oryzae (Sarocladium oryzae), Sphaerotheca graminis (S.attenuatum), Ustilago oryzae (Entyloma oryzae),
pyricularia grisea (Pyricularia grisea) on lawn and grain,
pythium spp on turf, rice, corn, cotton, oilseed rape, sunflower, sugar beet, vegetables and other plants,
Rhizoctonia species (Rhizoctonia sp.) (e.g., Rhizoctonia solani (r. solani)) on cotton, rice, potatoes, turf, corn, canola, potato, sugar beet, vegetables and other plants,
species of the genus Rynchosporium (e.g., r. secalis) on rice and cereals,
sclerotinia species (Sclerotinia sp.) (e.g., Sclerotinia (s.sclerotiorum)) on canola, sunflower, and other plants,
septoria tritici (Septoria tritici) and Septoria nodorum (Stagonospora nodorum) on wheat,
erysiphe (Erysiphe) (synonym, Uncinula necator) on grapevine,
genus Ustilago (Setospora sp.) on maize and turf,
ustilago filiformis (Sphacelotheca reilinia) on maize,
rhinocosoma species on soybean and cotton (Thievaniopsis sp.),
tilletia sp on cereals,
ustilago sp on cereals, maize and sugar beets, and
venturia sp (scab) on apples and pears (e.g., Venturia inaequalis on apples).
In yet another aspect, the present invention provides a method for controlling fungal infestation at a locus, the method comprising applying to the locus picoxystrobin crystal modification I as described above.
In yet another aspect, the present invention provides the use of picoxystrobin crystalline modification I as described above in controlling fungal infestation.
As used herein, the term "about" when used in conjunction with a numerical quantity or range means slightly greater than or slightly less than the numerical quantity or range, plus or minus 10% of the endpoints of the numerical quantity or range.
The term "room temperature" as used herein refers to a temperature range from about 20 ℃ to 26 ℃.
Drawings
Fig. 1 is an X-ray powder diffraction pattern of picoxystrobin crystal modification I of the present invention;
FIG. 2 is an IR spectrum of picoxystrobin crystal modification I of the invention;
FIG. 3 is a Differential Scanning Calorimetry (DSC) spectrum of picoxystrobin crystal modification I of the invention;
fig. 4 shows the crystal structure of picoxystrobin crystal modification I of the present invention; and is provided with
Fig. 5 is an X-ray powder diffraction pattern of amorphous picoxystrobin as obtained in example 1 below.
Detailed Description
Embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings.
In the following examples, percentages are by weight unless otherwise indicated.
Examples
Example 1 preparation of amorphous picoxystrobin
For comparison purposes picoxystrobin was prepared using the method disclosed in US 6,015,905. The details of the procedure followed are as follows:
Gaseous hydrogen chloride (HCl) was bubbled through a solution of 3-isochromanone (2.0g, 13.5 mmol) in methanol (30mL) for 0.5 h at room temperature. The solution was further stirred for an additional 2 hours. Methanol was removed under reduced pressure and the resulting residue was dissolved in dichloromethane. The insoluble material present was removed by filtration, after which the solution was dried by diafiltration on calcium carbonate to remove water. Finally, the solvent was removed to give methyl 2-chloromethylphenylacetate as an oil (2.62g, 98%), which was used in the next step without further purification.
A mixture of 2-hydroxy-6-trifluoromethylpyridine (2.0g, 12.3mmol), sodium hydroxide (0.52g, 12.9mmol) and 15-crown-5 (1 drop) in dry toluene (25mL) was stirred at reflux for 2 hours. Toluene was removed under reduced pressure and the white salt residue was dissolved in anhydrous Dimethylformamide (DMF) (15 mL). Methyl 2-chloromethylphenylacetate (2.44g, 12.3mmol) was added dropwise to anhydrous DMF (15mL) along with sodium iodide (10 mg). The mixture was stirred at 75 ℃ for 2 hours, then poured into water and extracted with ether. The ether extract was washed with water, dried, and the remaining ether was removed in vacuo to leave an oil which was purified by column chromatography (silica gel eluted with 10% ethyl acetate in hexanes) to give methyl 2- (6-tris-fluoromethylpyridin-2-yloxymethyl) phenyl acetate (3.3g, 83%).
Sodium methoxide (0.725g, 13mmol) and methyl formate (0.8mL, 13mmol) were added portionwise to a stirred solution of methyl 2- (6-trifluoromethylpyridin-2-yloxymethyl) phenyl acetate (2.0g, 6.0mmol) in anhydrous toluene (15mL) at room temperature under nitrogen. After 6 hours at room temperature, the mixture was poured into water and extracted with diethyl ether. The ether extract was washed with water, dried, and then the ether was removed to give (E) -methyl 2- [2- (6-trifluoromethylpyridin-2-yloxymethyl) phenyl ] -3-hydroxyacrylate (95% purity) as a yellow gum which was used in the next stage without further purification.
Dimethyl sulfate (0.65mL, 6.9mmol) was added dropwise to a mixture of (E) -methyl 2- [2- (6-trifluoromethylpyridin-2-yloxymethyl) phenyl ] -3-hydroxyacrylate (2.12g, 6mmol) and anhydrous potassium carbonate (1.2g, 8.7mmol) in anhydrous DMF (10 mL). After stirring at room temperature for 6 hours, the mixture was poured into water and extracted with diethyl ether. The ether extract was washed with water, dried, and then concentrated to give a crude product. The crude product was purified by column chromatography (silica gel eluted with 20% ethyl acetate in hexanes) to yield amorphous (E) -methyl 2- [2- (6-trifluoromethylpyridin-2-yloxymethyl) phenyl ] -3-methoxyacrylate (98% purity).
The product was analyzed using an X-ray powder diffractometer. Figure 5 shows that the X-ray powder diffraction pattern of the product has no significant signal. The results show that the product is amorphous.
Example 2 preparation of picoxystrobin Crystal modification I (crystallization from isopropanol)
A 5g sample of amorphous picoxystrobin prepared in example 1 was charged into a flask containing 35mL of isopropanol. The mixture was stirred to produce a homogeneous suspension. The resulting suspension was slowly heated in a water bath at 50 ℃ for 20 to 25 minutes with stirring to obtain a clear solution. The reaction mixture was allowed to cool at room temperature. Crystals formed during the subsequent 45 to 50 hours. The resulting crystals were filtered and dried under vacuum at room temperature to remove residual traces of isopropanol from the crystals. The crystals were 98% pure and produced in a molar yield of 80% w/w.
The crystals were characterized by IR, powder X-ray and single crystal X-ray diffraction analysis and were found to be picoxystrobin crystal modification I as shown in figures 1 and 2.
The melting point of the product was measured by DSC. The starting temperature was 73.872 ℃ and the maximum peak temperature was 79.115 ℃.
FIG. 2 shows the characteristic peaks of picoxystrobin crystal modification I on the IR spectrum at 1704.95, 1629.04, 1577.46, 1352.22, 1258.08, 1201.97, 1124.12, 983.51 and 810.19 cm -1To (3).
The powder X-ray diffraction pattern of the crystals of picoxystrobin crystal modification I shows reflections as shown in figure 2 and these values are summarized in table 2 below.
TABLE 2 reflection of powder X-ray diffraction pattern of picoxystrobin crystal modification I
The characteristic data of the crystal structure of picoxystrobin crystal modification I are shown in table 3 below.
Table 3: crystallographic data of picoxystrobin crystal modification I
Wherein:
a, b, c is the length of the unit cell edge
Angle of unit cell
Z is the number of molecules in a unit cell
The crystal structure of picoxystrobin crystal modification I is shown in fig. 4.
Example 3 preparation of picoxystrobin Crystal modification I (crystallization from hexane and chloroform)
A5 g sample of amorphous picoxystrobin prepared in example 1 was charged into a flask containing 40mL hexane and chloroform (1: 1). The mixture was stirred until picoxystrobin dissolved to produce a clear solution. The solution was left undisturbed for several days at room temperature so that slow and stable crystallization occurred. The crystals formed were recovered by filtration.
The recovered crystals were characterized by IR, powder X-ray and single crystal X-ray diffraction analysis as described in example 2. The results are the same as those obtained in example 2, indicating that the solid product is picoxystrobin crystal modification I.
Formulation examples
Example 4 preparation of amorphous picoxystrobin suspending agent (SC)
Suspension (SC) formulations were prepared from the components shown in table 4 below.
All components were combined and mixed homogeneously. The resulting mixture was ground with Dyno-Mill (produced by Willy a. Bachofen AG) to obtain a suspension.
TABLE 4
Example 5 preparation of picoxystrobin Crystal modification I suspending agent (SC)
Suspension (SC) formulations were prepared from the components listed in table 5 below.
All components were combined and mixed homogeneously. The resulting mixture was ground with Dyno-Mill (produced by Willy a. Bachofen AG) to obtain a suspension.
TABLE 5
Example 6: comparative storage stability
Samples of the compositions prepared in examples 4 and 5 were stored at a temperature of 54 ℃ for 1 month, 3 months and 6 months. The steps followed were performed according to CIPAC MT 46.3.
The concentration of picoxystrobin was measured by HPLC at the end of each storage period. Aggregation was measured by observation. The initial concentration of picoxystrobin in each formulation was 25%.
The results are shown in Table 6 below.
TABLE 6
Note:
the degree of aggregation is indicated, where "+" indicates that a small amount of aggregation is observed, "+ ++++" indicates that a large amount of aggregation is observed, and "-" indicates that no aggregation is observed.
The results listed in table 6 show that the amorphous picoxystrobin product obtained according to the prior art procedure showed very poor storage stability, wherein the amount of picoxystrobin in the formulation was significantly reduced during the test and significant aggregation of the picoxystrobin active ingredient was observed. In contrast, picoxystrobin crystal modification I of the present invention showed little degradation of the picoxystrobin active ingredient and no aggregation was observed.
Claims (17)
1. A crystal modification I of picoxystrobin exhibiting the following reflections as 2 Θ values in an X-ray powder diffraction pattern recorded with Cu-ka radiation at 25 ℃:
2θ＝8.4613±0.2 (1)
2θ＝12.0227±0.2(2)
2θ＝12.7030±0.2(3)
2θ＝13.8834±0.2(4)
2θ＝14.5237±0.2(5)
2θ＝16.2243±0.2(6)
2θ＝16.3844±0.2(7)
2θ＝17.1247±0.2(8)
2θ＝17.6249±0.2(9)
2θ＝18.7653±0.2(10)
2θ＝20.3659±0.2(11)
2θ＝21.2663±0.2(12)
2θ＝22.0466±0.2(13)
2θ＝22.1466±0.2(14)
2θ＝22.9469±0.2(15)
2θ＝23.7272±0.2(16)
2θ＝24.1474±0.2(17)
2θ＝25.3278±0.2(18)
2θ＝25.6479±0.2(19)
2θ＝26.1681±0.2(20)
2θ＝26.7884±0.2(21)
2θ＝28.3890±0.2(22)
2θ＝31.0300±0.2(23)
2θ＝35.4117±0.2(24)。
2. crystalline modification I of picoxystrobin according to claim 1, wherein the X-ray diffraction pattern is the same as the pattern shown in figure 1.
3. Crystalline modification I of picoxystrobin according to claim 1, which exhibits characteristic bands at 1704.95, 1629.04, 1577.46, 1352.22, 1258.08, 1201.97, 1124.12, 983.51 and 810.19cm-1An IR spectrum of 32 scans and a resolution of 4cm-1Under the conditions of (1).
4. The picoxystrobin crystal modification I of claim 3, wherein the IR spectrum of the crystal modification I is the same as shown in figure 2.
5. Crystalline modification I of picoxystrobin according to claim 1, which exhibits a Differential Scanning Calorimetry (DSC) profile with an endothermic peak at 79.115 ℃ and an onset temperature of 73.872 ℃.
6. Crystalline modification I of picoxystrobin according to claim 5, wherein the Differential Scanning Calorimetry (DSC) spectrum is the same as shown in figure 3.
7. A method of forming crystalline modification I of picoxystrobin of claim 1, the method comprising:
i) providing a picoxystrobin solution in a solvent system comprising one or more solvents, wherein the solvent system is selected from chloroform-hexane, dichloromethane-hexane and alcohols;
ii) crystallizing the dissolved compound into a crystal modification I of picoxystrobin having the formula I; and is
iii) isolating the crystalline solid from the solvent system to produce crystalline modification I of picoxystrobin.
8. The method of claim 7, wherein the picoxystrobin is dissolved in the solvent system at a temperature from room temperature to the reflux temperature of the solution.
9. The method of claim 8, wherein the temperature is the reflux temperature of the solution.
10. The process of claim 7, wherein step (ii) is carried out using seeds of crystalline modification I present in the solution.
11. The method of claim 10, wherein the seed crystals are present in an amount of 0.005% to 0.5% by weight of the solution.
12. A fungicidal composition comprising picoxystrobin crystal modification I according to any one of claims 1 to 6.
13. The fungicidal composition of claim 12, wherein the composition is a formulation selected from the group consisting of: suspension (SC), dispersible agent (DC), Emulsifiable Concentrate (EC), emulsion seed dressing, Granules (GR) and Suspoemulsion (SE).
14. The fungicidal composition of claim 12, wherein the composition is a formulation selected from the group consisting of: oil-based suspensions (OD), Soluble Granules (SG), suspension dressings, Microgranules (MG) and water dispersible granules (WG).
15. The fungicidal composition according to claim 12 or 13, wherein the composition is a suspending agent (SC).
16. A method of controlling fungal infestation of a locus, the method comprising applying to an agricultural locus a crystalline modification I of picoxystrobin as defined in any of claims 1 to 6 or a fungicidal composition as defined in any of claims 12 to 15.
17. Use of picoxystrobin crystal modification I according to any one of claims 1 to 6 for the preparation of an agrochemical composition for controlling fungal infestation.
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| PCT/CN2017/071499 WO2017125010A1 (en) | 2016-01-19 | 2017-01-18 | Novel crystalline form of picoxystrobin, method of preparing and use of the same |
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| WO1997001538A1 (en) * | 1995-06-28 | 1997-01-16 | Zeneca Limited | Process for the preparation of 2-(6-substituted pyrid-2-yloxymethyl)phenylacetate |
| CN102115458A (en) * | 2010-11-25 | 2011-07-06 | 大连凯飞精细化工有限公司 | Synthesis method of 3-methoxy-2-aryl(methyl)acrylate compounds |
| CN103030598A (en) * | 2012-12-17 | 2013-04-10 | 上海禾本药业有限公司 | Method for preparing strobilurin fungicide |
| CN103626691A (en) * | 2013-11-11 | 2014-03-12 | 上海禾本药业有限公司 | Picoxystrobin preparation method |
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| CN104151233A (en) * | 2014-08-25 | 2014-11-19 | 浙江泰达作物科技有限公司 | Preparation method of agricultural bactericide |
| CN104230794A (en) * | 2014-08-25 | 2014-12-24 | 浙江泰达作物科技有限公司 | Method for synthesizing high-efficiency green agriculture bactericide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997001538A1 (en) * | 1995-06-28 | 1997-01-16 | Zeneca Limited | Process for the preparation of 2-(6-substituted pyrid-2-yloxymethyl)phenylacetate |
| CN102115458A (en) * | 2010-11-25 | 2011-07-06 | 大连凯飞精细化工有限公司 | Synthesis method of 3-methoxy-2-aryl(methyl)acrylate compounds |
| CN103030598A (en) * | 2012-12-17 | 2013-04-10 | 上海禾本药业有限公司 | Method for preparing strobilurin fungicide |
| CN103626691A (en) * | 2013-11-11 | 2014-03-12 | 上海禾本药业有限公司 | Picoxystrobin preparation method |
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| BR112017023886A2 (en) | 2018-07-17 |
| AR107167A1 (en) | 2018-03-28 |
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| WO2017125010A1 (en) | 2017-07-27 |
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