CN117586328A

CN117586328A - Spinosad crystal forms, preparation method and application thereof

Info

Publication number: CN117586328A
Application number: CN202311006451.1A
Authority: CN
Inventors: J·T·布里斯托
Original assignee: Rotam Agrochem International Co Ltd
Current assignee: Meiaibao Asia Pacific Ltd
Priority date: 2022-08-12
Filing date: 2023-08-10
Publication date: 2024-02-23
Also published as: GB202211803D0; ES2963729R1; ES2963729A2; FR3138778A1; GB2621401A

Abstract

The present invention provides crystal modification I of spinosad. There is also provided a process for preparing crystal modification I of spinosad, the process comprising the steps of: i) Dissolving spinosad in a solvent system to form a spinosad solution; ii) precipitating a crystal modification I of spinosyn from the spinosyn solution; and iii) isolating the precipitated spinosyn in crystal modification I. Also provided are the use of crystal modification I of spinosad for controlling insect and mite infestations, and methods of controlling insects and mites using crystal modification I of spinosad.

Description

Spinosad crystal forms, preparation method and application thereof

The invention relates to spinosad crystal forms, a preparation method thereof and application thereof in agrochemical preparations.

Spinosad (Spinosad) is a broad spectrum of insecticides and acaricides. It was developed by the dow in 1995 and was first introduced as a commercial product. Spinosad is fully derived from fermentation of the soil bacterium spinosad (Saccharopolyspora spinosa). Spinosyns are active through a novel mode of action, primarily targeting binding sites on the nicotinic acetylcholine receptors (nachrs) of the insect nervous system. Spinosad is used to protect various commercial crops such as corn, soybean, cotton, various fruits, various vegetables such as potato, rice and turf, and is particularly useful for controlling cotton bollworms, tobacco budworms, armyworms and . Spinosad exhibits low toxicity and environmental characteristics similar to most biopesticides. Thus, spinosad is suitable for pest integrated management (IPM) and pesticide resistance management (IRM) programs.

Spinosyns are a combination of two spinosyns (spinosyns) of formula C ₄₁ H ₆₅ NO ₁₀ (Spinosyn A) and C ₄₂ H ₆₇ NO ₁₀ (Spinosyn D), chemical name (2R, 3aS,5aR,5bS,9S,13S,14R,16aS,16 bR) -2- (6-deoxy-2, 3, 4-tri-O-methyl-alpha-L-mannopyranosyloxy) -13- (4-dimethylamino-2, 3,4, 6-tetradeoxy-beta-D-erythropyranosyloxy) -9-ethyl-2, 3a, 5b,6,7,9,10,11,12,13,14,15,16a,16 b-hexadechydro-14-methyl-1H-as-benzobisindeno [3, 2-D)]Oxacyclododecene-7, 15-dione and (2S, 3aR,5aS,5bS,9S,13S,14R,16aS,16 bS) -2- (6-deoxy-2, 3, 4-tri-O-methyl-alpha-L-mannopyranosyloxy) -13- (4-dimethylamino-2, 3,4, 6-tetradeoxy-beta-D-erythropyranosyloxy) -9-ethyl-2, 3a, 5b,6,7,9,10,11,12,13,14,15,16a,16 b-hexadechydro-4, 14-dimethyl-1H-benzobisindeno [3,2-D ]]Oxacyclododecene-7, 15-dione. Spinosyns typically contain Spinosyn a and Spinosyn D, present in a ratio of 50 to 95 wt% Spinosyn a and 5 to 50 wt% Spinosyn D. Commercial formulations of spinosad typically employ a weight ratio of 85:15 Spinosyn a and Spinosyn D. Spinosad has the chemical structure:

wherein Spinosad a: r=h and Spinosad D: r=ch ₃ 。

Commercially available spinosyns are generally manufactured by the process described in EP 1 062 345 and exist in an amorphous state. Spinosyns in the amorphous state have been found to exhibit a high tendency to aggregate upon formulation, particularly during prolonged storage. Thus, commercially available spinosad is not well suited for use in economical formulations. There is a need to provide a technique for improving spinosyn formulations, in particular for increasing their storage stability.

A new stable spinosyn crystalline form has now been discovered which exhibits significantly improved properties. In particular, the new crystalline forms of spinosad exhibit higher stability and lower aggregation propensity when formulated, enabling the formulation to be stored for extended periods of time without degradation and loss of efficacy.

In a first aspect, the present invention provides a crystalline modification of spinosyn, hereinafter referred to as "crystalline modification I", which exhibits at least 3 reflections in any combination in an X-ray powder diffraction pattern (X-RPD) recorded using Cu-ka radiation at 25 ℃ in 2θ±0.20 degrees:

2θ ＝ 7.374 ± 0.20 (1)

2θ ＝ 9.565 ± 0.20 (2)

2θ ＝ 11.550 ± 0.20 (3)

2θ ＝ 11.823 ± 0.20 (4)

2θ ＝ 12.328 ± 0.20 (5)

2θ ＝ 15.433 ± 0.20 (6)

2θ＝15.822±0.20 (7)

2θ＝16.851±0.20 (8)

2θ＝17.482±0.20 (9)

2θ＝18.533±0.20 (10)

2θ＝19.993±0.20 (11)

2θ＝21.105±0.20 (12)

2θ＝23.078±0.20 (13)

2θ＝24.195±0.20 (14)

the spinosyn crystal modification I exhibits 3 of the above-mentioned reflections, preferably at least 4, more preferably at least 5, more preferably at least 6, more preferably at least 7, in particular at least 8 of the above-mentioned reflections.

In a preferred embodiment, the spinosyn of crystal modification I exhibits at least 3, preferably at least 4, more preferably at least 5, more preferably at least 6, more preferably at least 7, especially at least 8 or all of the following reflections in 2θ±0.20 degrees in any combination in an X-ray powder diffraction pattern recorded using cu—kα irradiation at 25 ℃):

2θ＝9.565±0.20 (2)

2θ＝11.550±0.20 (3)

2θ＝11.823±0.20 (4)

2θ＝15.433±0.20 (6)

2θ＝15.822±0.20 (7)

2θ＝16.851±0.20 (8)

2θ＝17.482±0.20 (9)

2θ＝19.993±0.20 (11)

2θ＝21.105±0.20 (12)

2θ＝24.195±0.20 (14)

in a preferred embodiment, crystal modification I of spinosad exhibits an X-ray powder diffraction pattern substantially as shown in figure 1.

In a second aspect, the present invention provides a crystal modification I of spinosyn, which exhibits a wavenumber (cm) in the infrared spectrum (IR) ^-1 (0.2%) 2930.01,2870.55,2824.68,1705.98 and 1659.87cm ^-1 Is characterized by functional group vibrational peaks.

In a preferred embodiment, crystal modification I of spinosad exhibits an infrared spectrum (IR) substantially as shown in fig. 2.

In a preferred embodiment, crystal modification I of spinosad shows an X-ray powder diffraction pattern according to the first aspect of the invention and an infrared spectrum (IR) according to the second aspect of the invention.

In a third aspect, the present invention provides a crystalline modification I of spinosyn which exhibits an endothermic melting peak in a Differential Scanning Calorimetry (DSC) profile with a peak maximum at 126.1 ℃ starting at 112.3 ℃, optionally further with a melting enthalpy of 24.56J/g.

In a preferred embodiment, crystal modification I of spinosad shows a Differential Scanning Calorimetry (DSC) profile substantially as shown in figure 3.

In a preferred embodiment, the spinosyn in crystal modification I shows an X-ray powder diffraction pattern according to the first aspect of the invention, and/or an infrared spectrum (IR) according to the second aspect of the invention and a Differential Scanning Calorimetry (DSC) pattern according to the third aspect of the invention.

In a preferred embodiment, the spinosyn of crystal modification I is characterized by an X-ray powder diffraction pattern substantially as shown in figure 1, and/or an infrared spectrum substantially as shown in figure 2, and/or a Differential Scanning Calorimetry (DSC) pattern substantially as shown in figure 3.

It has been found that crystal modification I of spinosad shows a significant improvement in its storage stability compared to the known form of spinosad, thereby significantly reducing the aggregation problems encountered with current commercial formulations. Furthermore, it has been found that the crystal modification I of spinosad exhibits a high degree of stability when formulated compared to amorphous spinosad prepared according to the disclosure of EP 1 062 345. In particular, the crystal modification exhibits a very low tendency to aggregate upon formulation. This in turn allows for the preparation of commercial formulations with improved properties, such as suspending agents (SC), including increased stability and improved efficacy. Furthermore, the crystal modification I of spinosad provides the formulation with an advantageously long shelf life due to its good stability.

Methods for preparing amorphous spinosad are well known in the art. Amorphous spinosad is manufactured and provided on a commercial scale. A particularly suitable method for preparing amorphous spinosad is described in EP 1 062 345.

In a fourth aspect, the present invention provides a process for preparing crystal modification I of spinosyn, comprising the steps of:

i) Dissolving spinosad in a solvent system to form a spinosad solution;

ii) precipitating a crystal modification I of spinosyn from the spinosyn solution; and

iii) The precipitated spinosyn was isolated as crystal modification I.

The present invention also provides a crystalline modification I of spinosyn obtainable by the process described hereinbefore, more preferably substantially as described in examples 2 or 3.

In step i) of the process, a spinosyn solution in a solvent system is prepared from a spinosyn starting material. Any suitable form of spinosad may be used as starting material. In a preferred embodiment, the spinosyn starting material in step i) is amorphous spinosyn.

The spinosyn solution is formed by dissolving spinosyn in a solvent system. The solvent system may consist of a single solvent or comprise a mixture of two or more solvents.

The solvent system may be formed from any suitable solvent that allows the crystal modification I of the spinosad to precipitate from solution. Suitable solvents may be selected from halogenated hydrocarbons such as benzotrifluoride, chlorobenzene, bromobenzene, dichlorobenzene, chlorotoluene and trichlorobenzene; ethers such as ethyl propyl ether, n-butyl ether, anisole, phenetole, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl glycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tertiary butyl ether, methyl tetrahydrofuran, dioxane, dichloro diethyl ether, ethylene oxide and/or propylene oxide; nitrated hydrocarbons, such as nitromethane, nitroethane, nitropropane, nitrobenzene, chloronitrobenzene, and o-nitrotoluene; aliphatic, alicyclic or aromatic hydrocarbons, for example pentane, octane, such as n-octane, nonane, ethylbenzene, mesitylene, cymene, hydrocarbon fractions having a boiling point of from 70 ℃ to 190 ℃, light petroleum oils (ligroin) and benzene; carbonates such as dimethyl carbonate, diethyl carbonate, dibutyl carbonate and ethylene carbonate; and mixtures thereof.

Preferably, the solvent system comprises one or more carbonates. Preferred carbonates are ethylene carbonate, dimethyl carbonate and mixtures thereof.

The dissolution of spinosad in step i) may be carried out at any suitable temperature. For example, the dissolution may be performed at ambient or room temperature, or at an elevated temperature. If an elevated temperature is used in step i), this temperature is preferably below the boiling point of the solvent system.

Preferably, the dissolution of spinosad in step i) is performed at a minimum temperature of 20 ℃, more preferably at least 30 ℃, more preferably at least 40 ℃. Depending on the solvent system used, the temperature may be up to 90 ℃, preferably up to 85 ℃, more preferably up to 80 ℃, more preferably up to 75 ℃. Suitable temperatures are temperatures of from 20 to 90 ℃, preferably from 30 to 90 ℃, more preferably from 30 to 80 ℃, even more preferably from 40 to 70 ℃, still more preferably from 40 to 60 ℃.

According to a preferred embodiment, the crystal modification I of spinosad is prepared by dissolving spinosad (preferably amorphous spinosad) in a solvent system comprising a solvent or a solvent mixture, by heating from ambient temperature to a temperature equal to or below the reflux temperature of the solvent system. In one embodiment, the spinosyn solution is prepared at the reflux temperature of the solvent system.

The dissolution of spinosad in step i) may be carried out by stirring, preferably by stirring and/or shaking.

In step ii) of the process, spinosyn in solution in a solvent system precipitates as crystal modification I. Any suitable technique may be used to precipitate spinosad from solution. Suitable techniques include one or a combination of cooling the solution, removing the solvent to concentrate the solution, adding reagents to reduce the solubility of spinosad in the solvent system, and seeding the solution.

In a preferred embodiment, the spinosyn solution prepared in step i) is cooled to ambient temperature or a temperature of about 0 to 30 ℃ to crystallize the desired crystalline form from the solvent system. In a preferred embodiment, the solution is cooled to a temperature of 20-25 ℃.

Cooling the solution to achieve the precipitation effect may be performed at any suitable rate. For example, the solution formed in step i) may be cooled at a rate of 0.5 to 3 ℃ per minute, preferably 1 to 2.5 ℃ per minute, for example about 2 ℃ per minute.

Crystal modification I of spinosad can be crystallized from a spinosad solution by concentrating the solution by removing the solvent system to a volume where spinosad precipitation occurs. Techniques for removing solvent systems from solutions are known in the art and include evaporating the solvent system, for example, under the application of reduced pressure or vacuum.

In one embodiment, the crystallization of the crystal modification I of spinosyn is obtained by adding seed crystals to the solution prepared in step I) of the process. The seed crystal is preferably a crystal of spinosad, more preferably a crystal of spinosad crystal modification I.

The amount of seed crystals added to the concentrated spinetoram solution is typically in the range of 0.001 to 10 wt%, more particularly in the range of 0.005 to 0.5 wt%, based on the weight of spinetoram used to prepare the concentrated solution in step (i). The seed crystals may be added to the solution at any suitable temperature and are preferably added to the concentrated solution at a temperature below the boiling point of the solvent system employed.

In step iii) of the process, the precipitated spinosyn is isolated from solution in crystal modification I. The crystalline material may be separated from the solution using any suitable technique. Suitable techniques include one or more of filtration, centrifugation, and decantation.

The spinosyn crystal modification I isolated from solution can be used directly. More preferably, the isolated crystalline solid is washed one or more times with a solvent. Preferably, the solvent employed in the washing stage is one or more components of the solvent system used to prepare the concentrated spinosyn solution in step i) as previously described. More preferably, the solvent system used for washing the isolated crystalline solid has the same composition as the solvent system used in step i) of the process.

The washing operation may be carried out at any suitable temperature to avoid significant loss of the crystalline material being washed, with preferred temperatures ranging from 0 ℃ to ambient or room temperature.

In one embodiment, the crystalline modification I of spinosyn isolated in step iii) is redissolved in a solvent system and recrystallized by repeating steps I) to iii) of the process.

The wash liquor and/or the solvent remaining after step iii) may be concentrated to obtain solid spinosad which may then be recycled for use in step i) of the process.

The spinosyn crystal modification I employed in the present invention and/or spinosyn crystal modification I obtained by the process of the present invention preferably has at least 05% by weight spinosyn crystal modification I, more preferably at least 98% by weight.

As described above, spinosad has insecticidal and acaricidal activity. Crystal modification I of spinosad showed this activity. Thus, in another aspect, the present invention provides an insecticidal/acaricidal composition comprising a crystal modification I of said spinosad and at least one adjuvant.

Spinosyns may be present in the composition in any suitable amount, depending on the type of formulation and/or the intended end use. Spinosad may be present in the composition in an amount of 1% by weight, preferably 5%, more preferably 10%, still preferably 15%, more preferably still 20%, in particular 25%, more in particular 30% by weight. Spinosad may be present in the composition in an amount of up to 90% by weight, preferably up to 80%, more preferably up to 75%, still preferably up to 70%, more preferably up to 65%, in particular up to 60%, more in particular up to 55% by weight. Spinosad may be present in the composition in an amount of 5-90 wt%, preferably 10-80%, more preferably 20-70%, more preferably 25-65%, more preferably 30-60%, in particular 40-50 wt%. In a preferred embodiment, spinosad is present in the composition in an amount of 45-50 wt%, especially 47-49%, more especially about 48 wt%.

The use of spinosad as an insecticide and acaricide is well known in the art and spinosad is used on a commercial scale. Crystal modification I of spinosad is also active in controlling insects and mites. As a result, techniques known in the art for formulating and applying spinosad for amorphous spinosad, such as disclosed in the prior art documents discussed previously herein, may also be applied in a similar manner to the crystalline modification I of spinosad of the present invention.

Thus, the present invention also provides a method of preparing a composition for controlling insects and acarids using the crystal modification I of spinosad.

Crystal modification I of spinosad may be used in any suitable formulation type. For example, the insecticidal/acaricidal composition may be in the form of a Suspension (SC), an oil-based suspension (OD), water-Soluble Granules (SG), a Dispersible (DC), an Emulsifiable Concentrate (EC), a seed-dressing emulsion (emulsion seed dressing), a seed-dressing suspension (suspension seed dressing), granules (GR), microgranules (MG), a Suspoemulsion (SE) or water dispersible granules (WG). Crystal modification I of spinosad may be included in these formulations in a known manner using suitable adjuvants known in the art.

In a preferred embodiment, the composition of the invention is in the form of a suspending agent (SC).

The aforementioned formulations can be prepared in a known manner by mixing the crystal modification I of spinosad with formulation components conventional in the art, such as one or more surfactants, liquid diluents, solid diluents, wetting agents, dispersants, thickeners, defoamers, antifreeze, preservatives, antioxidants, solid adhesion agents, inert fillers and other formulation ingredients.

The surfactant may be an ionic or nonionic emulsifier, dispersant or wetting agent. Examples that may be used include, but are not limited to, polyacrylates, lignosulfonates, phenylsulfonates or naphthalene sulfonates, polycondensates of ethylene oxide with fatty alcohols or fatty acids or fatty amines, substituted phenols (in particular alkylphenols), sulfosuccinates, taurine derivatives, in particular alkyl taurates, or phosphate esters of polyethoxylated phenols or alcohols.

Liquid diluents include, but are not limited to, water, N-dimethylamide, dimethylsulfoxide, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, propylene carbonate, dibasic esters, paraffin, alkylbenzene, alkylnaphthalene, glycerol triacetate, olive oil, castor oil, linseed oil, sesame oil, corn oil, peanut oil, cottonseed oil, soybean oil, rapeseed oil, and coconut oil, ketones such as 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, acetates such as hexyl acetate, heptyl acetate, and octyl acetate, and alcohols such as cyclohexanol, decanol, benzyl, and tetrahydrofurfuryl alcohol.

The solid diluent may be water soluble or non-water soluble. Water-soluble solid diluents include, but are not limited to, salts such as alkali metal phosphates, e.g., sodium dihydrogen phosphate, alkaline earth phosphates, sodium sulfate, potassium sulfate, magnesium sulfate and zinc sulfate, sodium chloride and potassium chloride, sodium acetate, sodium carbonate and sodium benzoate, and sugars and sugar derivatives, e.g., sorbitol, lactose, sucrose and mannitol. Examples of water insoluble solid diluents include, but are not limited to, clay, synthetic silica and diatomaceous earth, calcium and magnesium silicate, titanium dioxide, aluminum oxide, calcium oxide, and zinc oxide.

Wetting agents include, but are not limited to, alkyl sulfosuccinates, laurates, alkyl sulfates, phosphates, acetylene glycols, ethoxylated fluorinated alcohols, ethoxylated silicones, alkylphenol ethoxylates, benzenesulfonates, alkyl substituted benzenesulfonates, alkyl a-olefin sulfonates, naphthalenesulfonates, alkyl substituted naphthalenesulfonates, condensates of naphthalenesulfonates and alkyl substituted naphthalenesulfonates with formaldehyde, and alcohol ethoxylates. Polyalkylene glycol ethers are particularly useful for the compositions of the invention.

Dispersants include, but are not limited to, sodium, calcium and ammonium salts of lignosulfonates, which may optionally be polyethoxylated; sodium and ammonium salts of maleic anhydride copolymers; sodium salt of condensed phenolsulfonic acid; and naphthalene sulfonate-formaldehyde condensates. Of note are compositions comprising up to 10 wt% dispersant. Lignosulfonates, such as sodium lignin sulfonate, are particularly useful for the compositions of the present invention. Sodium alkyl naphthalene sulfonate formaldehyde condensates are particularly useful in the compositions of the present invention.

Thickeners include, but are not limited to guar gum, pectin, casein, carrageenan, xanthan gum, alginate, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and carboxymethyl cellulose. Synthetic thickeners include the former class of derivatives, as well as polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone, various polyethers, copolymers thereof, and polyacrylic acid and salts thereof. Xanthan gum is particularly useful for the compositions of the present invention.

Defoamers include all substances commonly used for this purpose in agrochemical compositions. Suitable defoamers are known in the art and are commercially available. Particularly preferred defoamers are mixtures of polydimethylsiloxane and perfluoroalkyl phosphonic acid, such as silicone defoamers available from GE or compton.

Preservatives include all substances in such agrochemical compositions which are commonly used for this purpose and are also well known in the art. Suitable examples which may be mentioned include(from Bayer Co.) and(from Bayer Co.).

Antioxidants include all substances commonly used for this purpose in agrochemical compositions known in the art. Butylated hydroxytoluene is preferred.

Solid adhesives include organic binders including tackifiers such as cellulose or substituted cellulose, natural and synthetic polymers in powder, granular or lattice form, and inorganic binders such as gypsum, silica or cement.

Inert fillers include, but are not limited to, natural ground minerals such as kaolin, alumina, talc, chalk, quartz, attapulgite, montmorillonite and diatomaceous earth, or synthetic ground minerals such as highly dispersed silicic acid, alumina, silicates and calcium phosphate and calcium hydrogen phosphate. Suitable particulate inert fillers include, for example, crushed and fractionated natural minerals such as calcite, marble, pumice, sepiolite and dolomite, or synthetic particles of inorganic and organic abrasive materials, as well as particles of organic materials such as sawdust, coconut shells, corncob and tobacco straw.

Suitable antifreeze agents are liquid polyols, such as ethylene glycol, propylene glycol or glycerol. The amount of antifreeze is generally from about 1 to about 20% by weight, in particular from about 5 to about 10% by weight, based on the total weight of the composition.

Biocides may also be included in the compositions of the present invention. Suitable biocides are biocides based on isothiazolinones, e.g. ICIOr Torl chemistry (Thor Chemie)>RS or Romen Hasi>MK. The amount of biocide is typically 0.05 to 0.5 wt% based on the total weight of the composition.

Other formulation ingredients may also be used in the present invention, such as dyes, defoamers, desiccants, and the like. These ingredients and their use are known to those skilled in the art and are commercially available.

As described above, the crystal modification I of spinosad of the present invention is active in controlling insects and mites.

Thus, in a further aspect, the present invention provides the use of crystal modification I of spinosad as described herein or a composition comprising crystal modification I of spinosad as described herein for controlling insects and acarids.

Still further, the present invention provides a method of controlling insect and/or mite infestations at a locus comprising applying to the locus a spinosyn crystal modification I as described above or a composition comprising spinosyn crystal modification I as described above.

Crystal modification I of spinosad may be used alone or in combination with one or more other active compounds, for example one or more insecticides, attractants, bactericides, acaricides, nematicides, fungicides, growth regulating substances, herbicides, safeners, fertilizers, semiochemicals or agents for improving plant properties. Crystal modification I of spinosad may be used in combination with one or more other active compounds in a single composition, as previously described. Alternatively, the crystalline modification I of spinosad may be employed in two or more compositions, in combination with one or more other active compounds.

Crystal modification I of spinosad may be used in combination with one or more inhibitors, which act to reduce the degradation of the active compound in the plant environment, on the surface of the plant parts or in the plant tissue after application.

Spinosad is the active ingredient of the insecticidal composition of the present invention and is effective against a range of insects. Crystal modification I of spinosad can be used to control insects such as Lepidoptera, including southern yellow beetle (Southern army worm), apple cabbage moth (codling moth), root cutting worm (cutworm), silverfish (shank moth), indian meal moth (Indian meal moth), leaf roller (leaf roller), corn ear moth (corn earworm), cotton bollworm (also called tomato fruit worm (Tomato fruit worm)), european corn borer (European corn borer), imported cabbage worm, cabbage looper (cabbage looper), cotton bollworm (pink bollworm), united states boll worm (American bolloworm), tomato angular worm (tomato horn worm), bag worm (bag worm), oriental moth (Eastern tent caterpillar), turf net moth (sound web worm), diamond back moth (diamond back moth), tomato leaf moth (tea leaf moth), grape berry moth (tea leaf moth), cabbage moth (leaf roller), cabbage moth (cabbage moth), cotton leaf worm (corn leaf worm), wheat leaf worm (yellow leaf worm et) and beet leaf worm (wheat leaf worm). Homoptera members, including Aphis gossypii leafhoppers (cotton aphid leafhopper), plant hoppers (plant hopper), pear psyllids (pearsyla), scale insects (scale insoles), whiteflies and foam hoppers (spittle bugs); diptera members, including houseflies, stings flies (stable flies), blowflies (blow flies) and mosquitoes; mites and ants. The compounds and formulations described herein are also useful for treating members of the order thysanoptera, including melon thrips and frankliniella occidentalis; coleopteran members, including Colorado potato beetles; a member of the order orthoptera; and lepidoptera (moths and butterflies), leaf miners, hymenoptera (She Juying (Leaf mining sawflies)), coleoptera (beetles), and diptera (true flies). Other pests that can be treated using the crystal modification I of spinosad include ants, green peach aphids, adult houseflies, western tent caterpillar larvae and spider mites (two-spotted spider mite).

The benefits of the present invention are particularly exhibited when the spinosad crystal modification I or insecticidal composition thereof is applied to kill insects or mites in a range of useful plant crops (especially corn, soybean, cotton, fruit, vegetables, potato, rice and turf) for control of cotton bollworms, tobacco budworms, armyworms and .

Crystal modification I of spinosad can be used to treat all plants and plant parts. In the present context, plants are understood to mean all plants and plant populations, for example wild plants or crop plants (including naturally occurring crop plants) which are desired and undesired. Crop plants may be plants which may be obtained by conventional breeding and optimization methods, biotechnology and genetic engineering methods or combinations of these methods, including transgenic plants and plant cultivars which may or may not be protected by the right of the plant breeder. Plant parts are understood to mean all parts and organs of plants above and below ground, such as shoots, leaves, needles, stalks, stems, flowers, fruit bodies, fruits, seeds, roots, tubers and rhizomes. Also included are harvested material as well as vegetative and reproductive propagation material, such as cuttings, tubers, meristems, rhizomes, side shoots, seeds, single and multiple plant cells and any other plant tissue.

The treatment of plants and plant parts with spinosad crystal modification I or a composition or formulation thereof may be carried out directly on the plants themselves or by allowing the composition or formulation to act on their surroundings, habitat or storage space. The plants may be treated by conventional treatment methods. Examples of such conventional treatment methods include dipping, spraying, vaporizing, atomizing, seeding, coating in the case of propagation material, and applying one or more coatings in the case of seeds.

In this specification, unless otherwise indicated, a property refers to a property measured at ambient conditions, i.e., at atmospheric pressure and a temperature of about 20 ℃.

If upper and lower limits are specified for a property, a range of values defined by a combination of any upper limit with any lower limit may also be implied.

As used herein, the term "about" or "approximately" when used with a numerical amount or range means slightly more or slightly less than the numerical amount or range and, for example, a range that deviates by ±10% from the end of the numerical amount or range.

The term "surrounding environment" as used herein refers to the locus where plants are growing, where plant propagation material of plants are being sown, or where plant propagation material of plants are to be sown.

As used herein, "precipitation" refers to the settling of solid material (precipitate) including the settling of crystalline material from a liquid solution, wherein the solid material is present in an amount greater than its solubility in the liquid solution.

All percentages are expressed as weight percent unless otherwise indicated.

Embodiments of the present invention are described in more detail below with reference to the attached drawing figures, wherein:

FIG. 1 is an X-ray powder diffraction pattern of crystal modification I of spinosad;

FIG. 2 is an Infrared (IR) spectrum of crystal modification I of spinosad;

FIG. 3 is a Differential Scanning Calorimetry (DSC) spectrum of crystal modification I of spinosad; and

fig. 4 is an X-ray powder diffraction pattern of amorphous spinosad.

Embodiments of the present invention will now be described by way of the following examples for illustrative purposes only.

All X-ray diffraction patterns were determined using powder diffractometer reflectance geometry at 25 ℃ using the acquisition parameters summarized in table 1 below:

TABLE 1

X' Pert Pro MPD from PANalytical B.V
	Theta compensation slit and graphite monochromator
Copper (K-alpha) irradiation, 40kV,40mA
	Step size 0.03 DEG 2-theta
Timing 1.0 seconds
	Maximum peak intensity 1705 counts per second
Scanning range is 3-60 degrees 2-theta

At 4cm ^-1 The resolution of (2) was measured by infrared spectroscopy and the number of scans of the crystalline sample was 16. As shown in FIG. 2, the wave number (cm ^-1 (0.2%) 2930.01,2870.55,2824.68,1705.98 and 1659.87cm ^-1 The characteristic functional group oscillation peak of (2) was confirmed as crystal modification I of spinosad.

All infrared spectra were obtained using the acquisition parameters summarized in table 2 below:

TABLE 2

All DSC profiles were obtained using the acquisition parameters summarized in table 3 below:

TABLE 3 Table 3

Examples

Example 1: preparation of amorphous spinosad according to EP 1 062 345, disclosure of example 1

The nutrient cultures of the spinosa strain NRRL18538 were grown in 50ml CSM medium (trypsin soybean broth 30g/l, yeast extract 3g/l, magnesium sulfate 2g/l, glucose 5g/l, maltose 4 g/l) in 250ml Erlenmeyer flasks, respectively, and shaken at 300rpm for 48 hours at 30 ℃. The fermentation culture contained 1ml of an inoculum of this nutrient culture in 7ml of INF202, INF202 being a proprietary medium similar to that described by Strobel & Nakatsukasa (1993).

Cultures were grown in 30ml plastic flasks arranged in 10x10 modules and shaken in a room at 30℃for 3, 5 or 7 days at 300 rpm. The broth (broth) was extracted with 4 volumes of acetonitrile and then analyzed by C-18 reverse phase column for Spinosad A+D by isocratic High Pressure Liquid Chromatography (HPLC) (Strobel and Nakatsukasa, 1993). The amount of spinosyn (spinosyn) present was determined from the absorbance at 250 nm. Spinosad a+d was determined from 10 fermentation flasks for each time point.

Two representative samples of each replicate group were also analyzed for pseudosugar-sensitive ligands (PSA) by a slightly modified HPLC system, a spinosyn precursor lacking Mao Longan (forosamine). In this system, the mobile phase is 35:35:30 acetonitrile/methanol/0.5% (w/v) ammonium acetate in water (R.Wijayarone, not disclosed).

The resulting spinosyn product was checked using X-ray powder diffraction. As shown in fig. 4, the X-ray powder diffraction pattern of the resulting spinosyn product had no significant signal, indicating that the spinosyn product prepared according to EP 1 062 345 was amorphous.

Example 2: preparation of spinosad crystal modification I

Crystallization from ethylene carbonate

10g of the amorphous spinosyn product prepared in example 1 was taken and placed in a 3-neck round bottom flask together with 50ml of ethylene carbonate, and the resulting slurry was heated to 85℃while stirring until spinosyn was completely dissolved. The resulting solution was slowly cooled at a rate of 2 ℃/min to a temperature of 20 to 25 ℃. After cooling, fine crystals were formed and the resulting heterogeneous mixture was stirred at 20 ℃ for 2 hours. Thereafter, the resulting slurry was filtered to separate solid materials, and washed with 3ml of ethylene carbonate at 20 ℃. The filtered crystals were dried under vacuum at 40 ℃.

The purity of the obtained crystal product is more than 98%, and the yield is not lower than 98%.

The resulting crystals were analyzed by infrared spectroscopy, X-ray powder diffraction and DSC and found to be crystal modification I of spinosad. The X-ray powder diffraction patterns, infrared spectra and DSC spectra are shown in FIGS. 1,2 and 3, respectively.

The infrared spectrum of crystal modification I is shown at wavenumber (cm ^-1 (0.2%) 2930.01,2870.55,2824.68,1705.98 and 1659.87cm ^-1 Is characterized by vibrations, as shown in fig. 2.

The DSC spectrum of crystal modification I showed an endothermic melting peak at 112.1℃and reached a maximum at 126.1℃with a melting enthalpy of 24.56J/g, as shown in FIG. 3.

The X-ray powder diffraction pattern of the crystal showed the reflections as shown in fig. 1, and the values of the critical reflections are summarized in table 4 below.

TABLE 4 Table 4

Example 3: preparation of spinosad crystal modification I

From carbonAcid dimethyl ester crystal

5g of the amorphous spinosyn product prepared in example 1 was taken and placed in a 3-neck round bottom flask together with 30ml of dimethyl carbonate, and the resulting slurry was heated to 75 ℃ while stirring until spinosyn was completely dissolved. The resulting solution was slowly cooled at a rate of 2 ℃/min to a temperature of 20-25 ℃. After cooling, fine crystals were formed and the resulting heterogeneous mixture was stirred at 20 ℃ for 2 hours. The resulting slurry was filtered and the isolated solid was washed with 3ml of dimethyl carbonate. The filtered crystals were dried under vacuum at 45 ℃.

The crystals were characterized by infrared spectroscopy, X-ray powder diffraction and DSC as crystal modification I of spinosad, as described in example 2.

Comparative example 1: precipitation of spinosad using fatty alcohols

Precipitation from methanol

5g of the amorphous spinosyn product prepared in example 1 was taken and placed in a 3-neck round bottom flask with 30ml of methanol and the resulting slurry was heated to 60℃while stirring until the spinosyn was completely dissolved. The resulting solution was slowly cooled at a rate of 2 ℃/min to a temperature of 20-25 ℃. After cooling, a precipitate formed and the resulting heterogeneous mixture was stirred at 20 ℃ for 2 hours. The resulting slurry was filtered and the isolated solid was washed with 3ml of methanol. The filtered precipitate was dried under vacuum at 45 ℃.

The purity of the obtained solid product is more than 95%, and the yield is not lower than 94%.

The solid product was identified as amorphous using X-ray powder diffraction.

Comparative example 2: precipitation of spinosad using ketones

Precipitation from acetone

5g of the amorphous spinosyn product prepared in example 1 was taken and placed in a 3-neck round bottom flask together with 30ml of acetone, and the resulting slurry was heated to 50℃while stirring until spinosyn was completely dissolved. The resulting solution was slowly cooled at a rate of 2 ℃/min to a temperature of 20-25 ℃. After cooling, a precipitate formed and the resulting heterogeneous mixture was stirred at 20 ℃ for 2 hours. The resulting slurry was filtered and the isolated solid was washed with 3ml of acetone. The filtered precipitate was dried under vacuum at 45 ℃.

The purity of the obtained solid product is more than 94%, and the yield is not lower than 94%.

The solid product was identified as amorphous using X-ray powder diffraction.

Formulation examples

Comparative example 3

Preparation of amorphous spinosad Suspension (SC)

All the components listed in table 5 below were mixed uniformly and the resulting mixture was ground with a Dyno-Mill (manufactured by Willy a.bachofen AG) to obtain a suspension.

TABLE 5

Example 4

Preparation of Suspension Concentrates (SC) of spinosad crystal modification I

All the components listed in table 6 below were mixed uniformly and the resulting mixture was ground with a Dyno-Mill (manufactured by Willy a.bachofen AG) to obtain a suspension.

TABLE 5

Example 5

Preparation of Suspension Concentrates (SC) of spinosad crystal modification I

TABLE 6

Comparative example 4

Preparation of spinosad Suspension (SC)

All the components listed in table 7 below were mixed uniformly and the resulting mixture was ground with a Dyno-Mill (manufactured by Willy a.bachofen AG) to obtain a suspension.

TABLE 7

Comparative example 5

Preparation of spinosad Suspension (SC)

All the components listed in table 8 below were mixed uniformly and the resulting mixture was ground with a Dyno-Mill (manufactured by Willy a.bachofen AG) to obtain a suspension.

TABLE 8

Comparison of storage stability

The storage stability of the compositions was tested using the procedure according to CIPAC MT 46.3. The process is as follows:

samples of the compositions prepared in examples 4 and 5 and comparative examples 3-5 were stored at 54℃for 1 month, 3 months and 6 months. The concentration of spinosyn in the composition was determined by High Pressure Liquid Chromatography (HPLC) at the end of each pot life. Aggregation of solid spinosyn particles was measured by observation.

The original concentration of spinosad in each formulation was 48 wt%. The results are summarized in table 9 below.

From the results shown in table 9 above, it can be seen that the Suspension (SC) formulations of examples 4 and 5 prepared using crystal modification I of spinosad exhibited excellent stability without loss of spinosad active ingredient, nor agglomeration of spinosad particles in suspension was detected. In contrast, the SC formulation of the comparative example exhibited significantly lower stability, significant loss of spinosad active ingredient, and significant agglomeration of spinosad particles in suspension.

Claims

1. Crystalline modification I of spinosad, which shows at least 3 reflections below any combination in an X-ray powder diffraction pattern (X-RPD) recorded using Cu-kα irradiation at 25 ℃, in 2θ±0.20 degrees:

2θ ＝ 7.374 ± 0.20 (1)

2θ ＝ 9.565 ± 0.20 (2)

2θ ＝ 11.550 ± 0.20 (3)

2θ ＝ 11.823 ± 0.20 (4)

2θ ＝ 12.328 ± 0.20 (5)

2θ ＝ 15.433 ± 0.20 (6)

2θ ＝ 15.822 ± 0.20 (7)

2θ ＝ 16.851 ± 0.20 (8)

2θ ＝ 17.482 ± 0.20 (9)

2θ ＝ 18.533 ± 0.20 (10)

2θ ＝ 19.993 ± 0.20 (11)

2θ ＝ 21.105 ± 0.20 (12)

2θ ＝ 23.078 ± 0.20 (13)

2θ ＝ 24.195 ± 0.20 (14)

2. the crystalline modification I of spinosyn of claim 1, which exhibits at least 3 reflections below in an X-ray powder diffraction pattern recorded using Cu-ka radiation at 25 ℃, in 2Θ ± 0.20 degrees:

2θ ＝ 9.565 ± 0.20 (2)

2θ ＝ 11.550 ± 0.20 (3)

2θ ＝ 11.823 ± 0.20 (4)

2θ ＝ 15.433 ± 0.20 (6)

2θ ＝ 15.822 ± 0.20 (7)

2θ ＝ 16.851 ± 0.20 (8)

2θ ＝ 17.482 ± 0.20 (9)

2θ ＝ 19.993 ± 0.20 (11)

2θ ＝ 21.105 ± 0.20 (12)

2θ ＝ 24.195 ± 0.20 (14)

3. crystal modification I of spinosad, which shows wavenumbers (cm) in the infrared spectrum (IR) ^-1 (0.2%) 2930.01,2870.55,2824.68,1705.98 and 1659.87cm ^-1 Is characterized by functional group vibrational peaks.

4. Crystalline modification I of spinosad, which shows an endothermic melting peak with a peak maximum at 126.1 ℃ starting at 112.3 ℃ in a Differential Scanning Calorimetry (DSC) spectrum.

5. The crystalline modification I of spinosyn of claim 1 or 2, further having an infrared spectrum (IR) according to claim 3 and/or a Differential Scanning Calorimetry (DSC) profile according to claim 4.

6. Crystalline modification I of spinosyn according to any of claims 1 to 5, having an X-ray powder diffraction pattern substantially as shown in figure 1, and/or an IR spectrum substantially as shown in figure 2, and/or a Differential Scanning Calorimetry (DSC) spectrum substantially as shown in figure 3.

7. A method of preparing crystal modification I of spinosad, the method comprising the steps of:

i) Dissolving spinosad in a solvent system to form a spinosad solution;

iii) The precipitated spinosyn was isolated as crystal modification I.

8. The method of claim 7, wherein the spinosad used in step i) is amorphous spinosad.

9. The method of claim 7 or 8, wherein the solvent system comprises a carbonate.

10. The method of claim 9, wherein the carbonate is ethylene carbonate, dimethyl carbonate, or a mixture thereof.

11. The method of any one of claims 7-9, wherein the precipitation of step ii) is accomplished by one or more of concentrating the solution by removing the solvent system from the solution, cooling the solution, adding a solubility-reducing agent, or adding seeds to the solution.

12. The method of claim 11, wherein a seed crystal is added to the solution, the seed crystal comprising crystal modification I of spinosad.

13. The method according to any one of claims 7-12, wherein step ii) is carried out by cooling to a temperature of 0-20 ℃.

14. Crystal modification I of spinosyn according to any of claims 1-6, obtainable by a process according to any of claims 9-13.

15. Crystal modification I of spinosad obtained as claimed in any of claims 7 to 13, having at least 98% by weight of crystal modification I of spinosad.

16. A composition comprising the spinosyn crystal modification I of any of claims 1-6 and 14 and at least one auxiliary.

17. The composition of claim 16, wherein the adjuvant is selected from one or more of the following: surfactants, liquid diluents, solid diluents, wetting agents, dispersants, thickeners, defoamers, antifreeze agents, preservatives, antioxidants, solid adhesion agents and inert fillers.

18. The composition of claim 16 or 17, which is in the form of a Suspension (SC), an oil-based suspension (OD), water-Soluble Granules (SG), a Dispersible (DC), a Emulsifiable Concentrate (EC), a seed-dressing emulsion, a seed-dressing suspension, granules (GR), a Microgranule (MG), a Suspoemulsion (SE) or a water dispersible granule (WG).

19. The composition of claim 18, wherein the composition is a suspending agent (SC).

20. The composition of any one of claims 16-19, comprising less than 75% by weight of spinosyn in crystal modification I.

21. The composition of claim 20 comprising 45-50 wt% of spinosyn in crystal modification I.

22. Use of a crystal modification I of spinosad according to any one of claims 1 to 6 or 14 or of a composition according to any one of claims 16 to 21 for controlling insects and acarids.

23. A method of controlling insects and acarids comprising applying to a plant, plant part, or locus thereof a crystal modification I of spinosad of any one of claims 1-6 or 14 or a composition of any one of claims 16-21.

24. The method of claim 23, wherein the plant is selected from the group consisting of corn, soybean, cotton, fruit, vegetable, potato, rice, and turf.

25. The method of claim 23 or 24, wherein the crystal modification I of spinosad is administered for controlling cotton bollworm, tobacco budworm, armyworm and .