Crystal forms of sulfoxaflor

Abstract

There is provided a composition of stereoisomers of sulfoxaflor in the form of a mixture having a crystal structure wherein the stereoisomers are selected from the diastereoisomers A and B in a selected A: B ratio and are water-soluble, a water solubility of at least about 0.7 + / -0.07 mg / ml, and a composition of stereoisomers of sulfoxaflor in the form of a mixture having a crystal structure. Methods of making the compositions and insecticide and / or agrochemical formulations comprising the compositions are also provided.

Description

Technical Field

[0001] This invention relates to sulfoxides, and more specifically, to sulfoxides with the chemical name {1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}(methyl)oxidized-λ 4 - Sulfonamide decanoate of flonicamid. More particularly, the present invention relates to polymorphs in compositions of stereoisomers of flonicamid in different proportions forming certain crystal structures, wherein such compositions are advantageously more soluble in water than present compositions; methods for preparing such compositions; and formulations / compositions comprising such compositions for use as pesticides, and more specifically as insecticides. Background Technology

[0002] Flupyradifurone is described in US9,125,412 as a mixture of diastereomers A and B.

[0003] Diastereomer A is the enantiomer {(R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-(R)-(methyl)oxidized-λ 4 -Sulfanamide decanoamide and {(S)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-(S)-(methyl)oxidized-λ 4 -A racemic mixture of sulfonamide decaneamides, and diastereomer B is the enantiomer {(R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-(S)-(methyl)oxidized-λ 4 -Sulfanamide decanoamide and {(S)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-(R)-(methyl)oxidized-λ 4 -A racemic mixture of sulfonamide decaneamides.

[0004] US9,125,412 mentions that the crude product purified by chromatography (chromatogram, 70% acetone / CH2Cl2) yielded sulfoxides (particularly flonicamid), as a 2:1 mixture of diastereomers. The substance is described as a colorless oil.

[0005] US 9,125,412 also mentions that flonicamid in a ratio of approximately 1:2 between diastereomeric groups A and B has been suspended in water with other substances, but it does not disclose how the 1:2 ratio was prepared or its physical properties. US 9,125,412 also describes that A:B mixtures in a ratio of 3:1 or higher are advantageously more stable and better suited for formulation. In fact, US 9,125,412 aims to extend the shelf life of flonicamid compositions with specific diastereomeric ratios because diastereomeric B naturally converts to diastereomeric A over time.

[0006] In addition, US9,125,412 describes the separation of an A:B mixture having a mixing ratio of approximately 1:2 and the conversion of the formulation with other components at high temperature for up to 100 hours in a formulation medium to a high percentage of diastereomer A.

[0007] The literature discloses three crystal structures of flonicamid, which are detailed below:

[0008] a) The crystal structure of (2R,3R)-flupyridine, stored in the CCDC database as 2088797, is published in General Environmental Science, Vol. 817, April 15, 2022, 153007. This structure, referred to in this application as "type 1a crystal," has the following crystal properties: (P 21 21 21(19), Cell:a 5.6473(5) (12) (2)

[0009] b) The crystal structure of (2S,3R)-flupyridine, published under 2088798 and stored in the CCDC database, is also published in General Environmental Science, Vol. 817, April 15, 2022, 153007. This structure, referred to in this application as "type 3b crystal," has the following crystal properties: (P 21(4), Cell:a5.8177(8)) (5) (17)

[0010] c) The crystal structure of (2R,3S)-flupyridine nitrile disclosed in Z. Kristallogr. NCS 2020; 235(4):861-862 (CCDC No.: 1986677). This structure, referred to as "Type 1b" in this application, has the following crystal properties: (P 21 / c(14), Cell:a 18.555(10) (4) (5)

[0011] Figure 1 , Figure 2 , Figure 3 and Figure 4 The XRPD patterns and DSC temperature spectra of the type 1a and type 1b crystals separated in this invention are shown. Figures 11 to 13 The calculated XRPD pattern of the isolated flonicamid nitrile isomer is shown.

[0012] In particular, Figure 11The XRPD pattern of the (2R,3R) isomer of flonicamid is shown, calculated from data stored in the CCDC database as 2088797. This structure is referred to as "type 1a crystal" in this application.

[0013] Figure 12 The XRPD pattern of the (2S,3R) isomer of flonicamid is shown, calculated from data stored in the CCDC database as 2088798. This structure is referred to as "3b type crystal" in this application.

[0014] Figure 13 The XRPD pattern of the (2R,3S) isomer of flonicamid is shown, calculated from data in CCDC No. 1986677. This structure is referred to as "type 1b crystal" in this application.

[0015] The flonicamid synthesized in this invention is a mixture of diastereomers. The DSC temperature spectrum of flonicamid isolated as type 1a crystals in this invention shows a melting peak with a maximum peak temperature at approximately 154-159 °C. The DSC temperature spectrum of flonicamid isolated as type 1b crystals in this invention shows a melting peak with a maximum peak temperature at approximately 125 °C.

[0016] Although A:B ratios of 3:1 and above are described as beneficial to formulation stability, it has been surprisingly found that a 3:7 A:B ratio of flonicamid is advantageous from a solubility perspective and can be used in both dry and wet formulations.

[0017] Therefore, one object of the present invention is to provide mixtures of different proportions of flupyradifurone stereoisomers that crystallize into crystal form, and these mixtures are more soluble in water than currently known flupyradifurone formulations.

[0018] Another object of the present invention is to provide a method for preparing mixtures of different proportions of flonicamid stereoisomers that crystallize into crystalline forms, and these mixtures are more soluble in water than currently known flonicamid formulations.

[0019] Another object of the present invention is to provide an insecticide formulation and composition comprising a mixture of different proportions of flupyradifurone stereoisomers that crystallize in a polymorphic combination, the mixtures being more soluble in water than flupyradifurone in currently known forms.

[0020] This and other objects and embodiments of the invention will become apparent during the description. Summary of the Invention

[0021] In one aspect, the present invention relates to mixtures of flupyradifurone stereoisomers crystallized in various polymorphic compositions, particularly having an isomer ratio such that such mixtures are advantageously more soluble in water than currently known mixtures of flupyradifurone stereoisomers.

[0022] In another aspect, the present invention relates to a method for preparing mixed crystals comprising flupyradifurone stereoisomers crystallized in various polymorphs and diastereomeric compositions, wherein the ratio between the isomers makes the mixture advantageously more soluble in water than mixtures of flupyradifurone stereoisomers currently known.

[0023] In one embodiment, the present invention provides a mixture of stereoisomers of flonicamid having a predominant diastereomer A content (about 90-96%), the mixture crystallizing in a mixed crystal form (Y-type), comprising known type 1a crystals and a novel crystalline phase. The novel crystalline phase always crystallizes in the same proportion as the type 1a crystals, producing a constant XRPD pattern. The Y-type has higher solubility than the known type 1a crystals.

[0024] This novel crystalline phase is called Yn and can be characterized by the following X-ray diffraction peaks:

[0025] 2θ is 15.5°, 16.3°, 17.4°, 19.4°, 21.3°, 22.7° ± 0.2°.

[0026] In addition, Yn-type crystals have the following crystal structure parameters:

[0027]

[0028] Figure 14 The calculated XRPD pattern of a Yn-type crystal is shown. Crystal structure parameters were extracted and calculated from the XRPD of crystal Y, which is a mixture of Yn-type and known 1a-type crystals. Table I below further details the XRPD peaks of the Y-type crystal, classified according to its composition, 1a-type crystal structure, and the novel Yn phase.

[0029] XRPD peaks of type IY crystals

[0030]

[0031] In yet another embodiment, the present invention provides a mixed X-type crystal comprising stereoisomers of flonicamid, with diastereomeric ratios A:B between 3:7 and 2:8, and shows a DSC temperature spectrum with a single melting peak having a maximum peak temperature in the range of approximately 114-119 °C. Fluonicamid X-type crystals exhibit high water solubility.

[0032] In another embodiment, the present invention provides a mixture of stereoisomers with a purity of 90%, preferably 94%, more preferably 98%, and even more preferably 99% ± 1% for the crystalline diastereomer A.

[0033] In another embodiment, the present invention provides a direct crystallization process for separating a mixture of stereoisomers of diastereomer A with a purity increased by 90%, preferably 94%, more preferably 98%, and even more preferably 99% ± 1%. In particular, this process avoids the preparation of complex formulations requiring prolonged storage at high temperatures, as described in Table 3 of US 9,125,412.

[0034] In yet another embodiment, the present invention provides a direct crystallization process for producing X and Y type crystals and pure diastereomer A, which are advantageously more soluble in water than currently known crystalline flonicamid formulations. In particular, the present invention provides a method for preparing Y and X type crystals of flonicamid and pure diastereomer A, wherein this method is selected from quenching, solvent-antisolvent, mother liquor evaporation, and crystallization during a filtration process for crystallizing these forms of flonicamid.

[0035] In yet another specific embodiment, the quenching method includes:

[0036] The raw material of flonicamid is dissolved in a solvent;

[0037] Heating and stirring the solution of flonicamid;

[0038] The solution was rapidly cooled in an ice bath at a temperature of 0 to 5°C.

[0039] Prepare a suspension of Y-type or pure diastereomer A; and

[0040] Separating solid substances from a suspension.

[0041] In another specific embodiment, mother liquor evaporation is used to prepare type X of a composition comprising diastereomers A and B, wherein a solvent / antisolvent pair or a single solvent is used. Type X crystals crystallize from the mother liquor, and the main phase crystallizes from and separates from the mother liquor. Specifically, the solvent / antisolvent pair is selected from dichloromethane / heptane and 96% ethanol / water, and the single solvent used is selected from tert-butyl methyl ether, dichloroethane, and isopropyl acetate.

[0042] Methods for producing X-type crystals include:

[0043] The main phase is crystallized and separated from the mother liquor;

[0044] Evaporating the mother liquor and allowing new solid substances to crystallize in the suspension; and

[0045] Alternatively, new solid substances can be separated from the suspension.

[0046] Specifically, the mother liquor used to produce type X includes:

[0047] The raw material of flonicamid is dissolved in a solvent;

[0048] Heating and stirring the solution of flonicamid;

[0049] cooling solution;

[0050] After cooling, the antisolvent is added dropwise to the solution, wherein the antisolvent is cooled in an ice bath;

[0051] Stir the antisolvent in the solution until a suspension is formed; and

[0052] Processing solid substances from suspensions.

[0053] In another specific embodiment, the separation or treatment of solid matter is selected from filtration, sedimentation and decantation, evaporation and centrifugation.

[0054] In yet another specific embodiment, the solvent-antisolvent method includes:

[0055] The raw material of flonicamid is dissolved in a solvent;

[0056] Heating and stirring the solution of flonicamid;

[0057] cooling solution;

[0058] After cooling, the antisolvent is added dropwise to the solution, wherein the antisolvent is cooled in an ice bath; and

[0059] Stir the antisolvent in the solution until the solid substance crystallizes.

[0060] In another specific embodiment, the solvent-antisolvent method further includes separating the crystal form from the suspension, wherein the separation is selected from filtration, sedimentation and decantation, evaporation and centrifugation.

[0061] Insecticides and / or pesticide formulations, compositions and formulations that individually contain these crystal forms selected from X, Y and pure diastereomer A, or together or in combination with other insecticides and pesticide compounds, are also within the scope of this invention.

[0062] In yet another embodiment, the present invention provides a method for producing a novel crystalline phase of flonicamid, and the novel crystalline phase produced in this method. Specifically, this novel crystalline phase is produced using a mixture of crystal structures 1a of flonicamid, and advantageously provides it with higher water solubility than currently known crystal structures of flonicamid, mixtures of crystal structures, and their proportions.

[0063] Without departing from the scope and spirit of the invention, specific non-limiting examples and embodiments of the invention are described in detail below. Attached Figure Description

[0064] Figure 1 The XRPD pattern of type 1a crystals of flonicamid is shown.

[0065] Figure 2 The DSC temperature spectrum of type 1a crystals of flonicamid is shown.

[0066] Figure 3 The XRPD pattern of type 1b crystals of flonicamid is shown.

[0067] Figure 4 The DSC temperature spectrum of type 1b crystals of flonicamid is shown.

[0068] Figure 5 The XRPD pattern of Y-type crystals of flonicamid is shown.

[0069] Figure 6 XRPD comparison between Y-type and 1a-type crystals of flonicamid is shown.

[0070] Figure 7 The DSC temperature spectrum of Y-type crystals of flonicamid is shown.

[0071] Figure 8 The DSC temperature spectrum of X-type crystals of flonicamid is shown.

[0072] Figure 9 The XRPD pattern of X-type crystals of flonicamid is shown.

[0073] Figure 10 The XRPD pattern of flonicamid raw material is shown.

[0074] Figure 11 The calculated XRPD pattern of the crystal structure of (2R,3R)-flupyridine nitrile 2088797 is shown.

[0075] Figure 12 The calculated XRPD pattern of the crystal structure of (2S,3R)-flupyridine nitrile 2088798 is shown.

[0076] Figure 13 The calculated XRPD pattern of the crystal structure of (2R,3S)-flupyridine nitrile 1986677 is shown.

[0077] Figure 14 The calculated XRPD pattern of the novel crystalline phase Yn is shown. Detailed Implementation

[0078] Figures 1 to 10 X-ray diffraction patterns and thermal images are shown, which are characteristic of different crystalline forms of flonicamid prepared in this invention. As described above, three specific mixtures of stereoisomers of crystalline forms of particular interest for their water solubility have been produced, namely X-type and Y-type crystals and a pure diastereomeric isomer A. Their X-ray diffraction patterns and thermal properties are particularly evident in... Figure 1 and Figure 2 and Figures 5 to 9 The values ​​are detailed below.

[0079] Y-type crystal:

[0080] The novel Y-type crystal (a racemic mixture of R,R and S,S isomers) is characterized primarily by XRPD peaks at 2θ values ​​of 15.5°, 16.3°, 17.4°, 19.2°, and 26.0° ± 0.2°, as well as other peaks at 2θ values ​​of 19.4°, 20.0°, 21.3°, and 22.7° ± 0.2°.

[0081] The new Y-type crystal is also characterized by, for example Figure 5 The XRPD pattern shown. See also: Figure 6 Comparison of X-ray diffraction patterns between type 1a and type Y crystals of flupyradifurone.

[0082] The Y-type crystal is characterized by having a diastereomeric ratio of A:B of approximately 90% of the racemic mixture of diastereomeric A, preferably 92% of the total Y-type crystal content, more preferably 94%, and even more preferably 96% ± 1%.

[0083] The Y-type crystals exhibit a DSC temperature spectrum with a broad melting peak, the peak temperature of which is located in the range of 140-160 °C. For example... Figure 7 As shown, very small amounts of heat absorption are sometimes detected in the range of 100-115℃.

[0084] The solubility of Y-type crystals in water is approximately 1.2 ± 0.3 mg / ml, while the solubility of 1a-type crystals is approximately 0.7 ± 0.07 mg / ml.

[0085] In one particular embodiment, the ratio of diastereomers A and B in type 1a crystals with a solubility of 0.7 ± 0.07 mg / ml is 97:3.

[0086] X-type crystal:

[0087] Flupyradifurone in type X crystals containing diastereomer B is a racemic mixture of R,S and S,R isomers, between about 60% and 80%, preferably between 65% and 75%, more preferably between 70%, and exhibits a DSC temperature spectrum with a melting peak having a maximum peak temperature between about 114-119 °C. This maximum melting peak temperature is lower than the known maximum melting peak temperatures of type 1a and type 1b crystals. See also Figure 8 .

[0088] The solubility of X-type crystals in water is approximately 1.6 ± 0.3 mg / ml, while the solubility of 1a-type crystals is approximately 0.7 ± 0.07 mg / ml.

[0089] The X-type has such Figure 9 The XRPD pattern shown.

[0090] In one particular embodiment, the ratio of diastereomers A and B in type 1a crystals with a solubility of 0.7 ± 0.07 mg / ml is 97:3.

[0091] For comparison, it is noteworthy that at 20°C (Lewis, KA; Tzilivakis, J.; Warner, D.; and Green, A. (2016) International Database for Pesticide Risk Assessment and Management. Human and Ecological Risk Assessment: International Journal 22(4), 1050-1064. DOI: 10.1080 / 10807039.2015.1133242), the registered water solubility value of flonicamid is 568 mg / L, equivalent to approximately 0.57 mg / ml. That is, all forms of flonicamid in this invention have been shown to be advantageously more soluble in water than flonicamid in currently known formulations.

[0092] Crystallization of pure diastereomer A

[0093] In another embodiment, a direct crystallization process for separating pure diastereomer A from a mixture of diastereomers A and B is disclosed, wherein the content of pure diastereomer A is 90% of the total content, preferably 94%, more preferably 98%, and even more preferably 99% ± 1%. These processes avoid the preparation of complex formulations requiring long-term storage at high temperatures as described in Table 3 of US 9,125,412. The pure diastereomer A separated from this crystallization crystallizes as type 1a crystals. These processes include rapid quenching crystallization and solvent / antisolvent crystallization.

[0094] The process for preparing different X and Y type crystals and pure diastereomer A of flonicamid nitrile according to the present invention is described below, the features of which are described in detail above and in the accompanying drawings.

[0095] process

[0096] raw material

[0097] According to WO2008 / 057129, flonicamid raw materials were synthesized by oxidizing sulfonamide-decaneamide with m-CPBA, and the diastereomeric ratio A:B was 61:37. See also... Figure 10 The XRPD pattern points to a mixture of type 1a and type 1b crystals. See also the detailed description above. Figures 11 to 13 XRPD patterns of isolated isomers of flupyradifurone in [the study].

[0098] Preparation of Y-type crystals

[0099] Example 1 - Preparation of Y-type crystals

[0100] 300 mg of flonicamid was dissolved in 7 mL of chloroform by heating to 80 °C and stirring at 400 rpm. The resulting solution was rapidly cooled using an ice bath (0–5 °C). Crystallization was observed after 10 minutes. The solid was separated from the suspension by vacuum filtration. The ratio of diastereomers A:B obtained was 91:9. The maximum DSC peak temperatures were 108 °C (small peak) and 148 °C.

[0101] Example 2 - Preparation of Y-type crystals

[0102] 300 mg of flonicamid was dissolved in 30 mL of toluene by heating to 110 °C and stirring at 400 rpm. The resulting solution was rapidly cooled using an ice bath (0–5 °C). Crystallization was observed after 10 minutes. The suspension was filtered by vacuum filtration. The ratio of diastereomers A:B obtained was 88:12. The maximum DSC peak temperatures were 111 °C (small peak) and 154 °C.

[0103] Example 3 - Preparation of Y-type crystals

[0104] 500 mg of flonicamid was dissolved in 20 mL of chloroform (25 mL round-bottom flask) by heating to 80 °C and stirring at 400 rpm. The resulting solution was rapidly cooled using an ice bath (0–5 °C). Crystallization was observed after 5 minutes. The suspension was filtered by vacuum filtration. The ratio of diastereomers A:B obtained was 96:4. The maximum DSC peak temperature was 150 °C.

[0105] Example 4 - Preparation of Y-type crystals

[0106] 500 mg of flonicamid was dissolved in 5 mL of dichloroethane (in a 25 mL round-bottom flask) by heating to 80 °C and stirring at 400 rpm. The resulting solution was rapidly cooled using an ice bath (0–5 °C). Crystallization was observed after 5 minutes. The suspension was filtered by vacuum filtration. The ratio of diastereomers A:B obtained was 93:7. The maximum DSC peak temperatures were 110 °C (small peak) and 149 °C.

[0107] Example 5 - Preparation of Y-type crystals

[0108] 300 mg of flonicamid was dissolved in 3 mL of dichloromethane by heating to 80 °C and stirring at 400 rpm. The resulting solution was rapidly cooled using an ice bath (0–5 °C). Crystallization was observed after 5 minutes. The suspension was filtered by vacuum filtration. The ratio of diastereomers A:B obtained was 90:10. The maximum DSC peak temperatures were 111 °C (small peak) and 150 °C.

[0109] Example 6 - Preparation of Y-type crystals

[0110] 300 mg of flonicamid was dissolved in 5 mL of 96% ethanol by heating at approximately 60 °C and stirring at 400 rpm. Heating was then stopped. 10 mL of cooled heptane (in an ice bath) was then added in portions to the heated solution. Crystallization was observed during the addition of the antisolvent and then separated by vacuum filtration. The ratio of diastereomers A:B obtained was 95:5. The maximum DSC peak temperatures were 112 °C (small peak) and 158 °C.

[0111] Example 7 - Preparation of Y-type crystals

[0112] 300 mg of flonicamid was dissolved in 3 mL of 96% ethanol by heating to boiling point and stirring at 400 rpm. Heating was then stopped. 6 mL of cooled isopropanol (in an ice bath) was added in portions to the resulting solution. Crystallization began immediately upon addition of isopropanol. The solution was then stirred for 10 minutes and separated by vacuum filtration. The ratio of diastereomers A:B obtained was 96:4. The maximum DSC peak temperature was 159 °C.

[0113] Example 8 - Preparation of Y-type crystals

[0114] 506 mg of flonicamid was dissolved in 8 mL of 96% ethanol by heating to 60 °C and stirring at 400 rpm. Heating was then stopped. 16 mL of cooled heptane (in an ice bath) was added dropwise to the resulting solution over 30 minutes. Crystallization began after approximately 5 mL of heptane was added. 2 mL of the resulting suspension was filtered after 5 minutes of crystallization. The suspension was then filtered after stirring at RT (400 rpm) for 3 hours. The ratio of diastereomers A:B obtained was 93:7. The peak DSC temperature was 159 °C.

[0115] Example 9 - Preparation of Y-type crystals

[0116] 300 mg of flonicamid was dissolved in 3 mL of ethyl acetate by heating to 60 °C and stirring at 400 rpm. Heating was then stopped. 3 mL of cooled heptane (in an ice bath) was added in portions to the resulting solution. Crystallization immediately began upon the addition of heptane. The solution was then stirred for 10 minutes and separated by vacuum filtration. The ratio of diastereomers A:B obtained was 92:8. The maximum DSC peak temperatures were 112 °C (small peak) and 153 °C.

[0117] Example 10 - Preparation of Y-type crystals

[0118] 300 mg of flonicamid was dissolved in 3 mL of 96% ethanol by heating and stirring (400 rpm) at approximately 67 °C. Heating was then stopped. 12 mL of cooled tert-butyl methyl ether (in an ice bath) was then added in portions to the heated solution. Crystallization was observed 10 minutes after the addition of the antisolvent, and then separated by vacuum filtration. The ratio of diastereomers A:B obtained was 93:7. The maximum DSC peak temperature was 160 °C.

[0119] Example 11 - Preparation of Y-type crystals

[0120] 300 mg of flonicamid was dissolved in 3 mL of n-butyl acetate by heating to approximately 90 °C and stirring at 400 rpm. Heating was then stopped. 12 mL of cooled isopropanol (in an ice bath) was added in portions to the resulting solution. No crystallization was observed after stirring at RT for 15 minutes. The solution was then cooled in an ice bath. Crystallization was observed within 5 minutes of stirring. The solution was stirred for 10 minutes and then separated by vacuum filtration. The ratio of diastereomers A:B obtained was 93:7. The maximum DSC peak temperature was 158 °C.

[0121] Preparation of X-type crystals

[0122] Example 12 - Preparation of X-type crystals

[0123] 300 mg of flonicamid was weighed into a 10 mL glass bottle and mixed in a shaker at RT and 400 rpm, with 3 mL of dichloromethane added in 0.5 mL portions every 15 minutes. The substance partially dissolved. The resulting suspension was maintained by mixing in a shaker at RT and 400 rpm. The suspension was filtered under vacuum to remove the solids, and the mother liquor was allowed to evaporate slowly. Crystallization was observed within 1 day. Fresh solids were filtered under vacuum. The ratio of diastereomers A:B obtained was 26:72. The maximum DSC peak temperature was 117 °C.

[0124] Example 13 - Preparation of X-type crystals

[0125] 30 mL of tert-butyl methyl ether was added in portions to 300 mg of flonicamid by heating to 80 °C for 15 minutes with stirring at 400 rpm. The substance did not completely dissolve. The suspension was filtered under vacuum, and the solids were treated. The mother liquor was slowly evaporated at RT. Crystallization was observed, and after 6 days, the new solids were separated by vacuum filtration. The ratio of diastereomers A:B obtained was 25:75. The maximum DSC peak temperature was 116 °C.

[0126] Example 14 - Preparation of X-type crystals

[0127] 300 mg of flonicamid was dissolved in 9 mL of dichloromethane by heating at approximately 50 °C and stirring at 400 rpm. Heating was then stopped. 9 mL of cooled heptane (in an ice bath) was then added in portions to the heated solution. Crystallization was observed during the addition of the antisolvent, and the solids were filtered and processed by vacuum filtration. The mother liquor was held at RT. The new solids crystallized over 24 hours and were separated by vacuum filtration. The diastereomers A:B obtained were in a ratio of 32:68. The maximum DSC peak temperature was 115 °C.

[0128] Example 15 - Preparation of X-type crystals

[0129] 300 mg of flonicamid was dissolved in 3 mL of 96% ethanol by heating at approximately 67 °C and stirring at 400 rpm. Heating was then stopped. 6 mL of cooling water (in an ice bath) was then added in portions to the heated solution. Crystallization was observed during the addition of the antisolvent. The solids were separated and processed by vacuum filtration. The mother liquor was kept in a sealed vial at RT and crystallized over 2 h. The new solids were filtered off by vacuum filtration. The ratio of diastereomers A:B obtained was 28:71. The maximum DSC peak temperature was 114 °C.

[0130] Example 16 - Preparation of X-type crystals

[0131] The mother liquor after filtration of the sample prepared according to Example 4 was retained, and the liquid was allowed to evaporate slowly. The solid material crystallized over 2 weeks and was then filtered by vacuum filtration. The ratio of diastereomers A:B obtained was 31:67. The maximum DSC peak temperature was 119°C.

[0132] Example 17 - Preparation of X-type crystals

[0133] The substance from the mother liquor of Example 9 crystallized during filtration. The solid substance was filtered. The ratio of diastereomers A:B obtained was 19:81. The maximum DSC peak temperature was 115°C.

[0134] Example 18 - Preparation of X-type crystals

[0135] 300 mg of flonicamid was dissolved in 3 mL of isopropyl acetate by heating to 100 °C and stirring at 400 rpm. The resulting solution was rapidly cooled using an ice bath (0–5 °C). Crystallization was observed after 5 minutes. The suspension was further filtered by vacuum filtration, and the solids were treated. The mother liquor was allowed to evaporate slowly. Crystallization was observed within 5 days, and the new solids were then separated by vacuum filtration. The ratio of diastereomers A:B obtained was 31:69.

[0136] Preparation of pure diastereomer A

[0137] Example 19 - Preparation of pure diastereomer A - Rapid cooling in methanol

[0138] 300 mg of flonicamid was dissolved in 3 mL of human methanol by heating to 70 °C and stirring at 400 rpm. The resulting solution was rapidly cooled using an ice bath (0–5 °C). Crystallization was observed after 15 minutes. The suspension was filtered by vacuum filtration. The ratio of diastereomers A:B obtained was 92:8.

[0139] Example 20 - Preparation of pure diastereomer A - Rapid cooling in ethyl acetate

[0140] 300 mg of flonicamid was dissolved in 3 mL of ethyl acetate by heating to 70 °C and stirring at 400 rpm. The resulting solution was rapidly cooled using an ice bath (0–5 °C). Crystallization was observed after 5 minutes. The suspension was filtered by vacuum filtration. The ratio of diastereomers A to B obtained was 89:10.

[0141] Example 21 - Preparation of pure diastereomer A - Rapid cooling in methyl isobutyl ketone

[0142] 300 mg of flonicamid was dissolved in 3 mL of methyl isobutyl ketone by heating to 70 °C and stirring at 400 rpm. The resulting solution was rapidly cooled using an ice bath (0–5 °C). Crystallization was observed after 10 minutes, and the solid was then separated by vacuum filtration. The ratio of diastereomers A to B obtained was 87:13.

[0143] Example 22 - Preparation of pure diastereomer A-acetone / water

[0144] At RT, 300 mg of flonicamid was dissolved in 3 mL of acetone and stirred at 400 rpm. Then, 6 mL of water was added in portions. After stirring at RT for 1 minute, crystallization was observed, and the solid was then separated by vacuum filtration. The ratio of diastereomers A:B obtained was 97:3.

[0145] Example 23 - Preparation of pure diastereomer A-acetonitrile / water

[0146] At RT, 300 mg of flonicamid was dissolved in 3 mL of acetonitrile and stirred at 400 rpm. Then, 6 mL of water was added in portions. Crystallization was observed after stirring at RT for 1 minute, and the solid was then separated by vacuum filtration. The ratio of diastereomers A:B obtained was 99:1.

[0147] Example 24 - Preparation of pure diastereomer A-acetone / tert-butyl methyl ether

[0148] At RT, 500 mg of flonicamid was dissolved in 5 mL of acetone and stirred at 400 rpm. Then, 20 mL of tert-butyl methyl ether was added in portions. Crystallization was observed after stirring at RT for 2 minutes, and the solid was then separated by vacuum filtration. The ratio of diastereomers A:B obtained was 98:2.

[0149] Example 25 - Preparation of pure diastereomer A-tetrahydrofuran / water

[0150] 300 mg of flonicamid was dissolved in 3 mL of tetrahydrofuran by heating and stirring (400 rpm) at approximately 70 °C. Heating was then stopped. 9 mL of cooled water (in an ice bath) was then added in portions to the heated solution. Crystallization was observed during the addition of the antisolvent, and the solid was then separated by vacuum filtration. The ratio of diastereomers A:B obtained was 96:4.

[0151] Example 26 - Preparation of pure diastereomer A - 96% ethanol / isopropanol

[0152] 300 mg of flonicamid was dissolved in 3 mL of 96% ethanol by heating to boiling point and stirring at 400 rpm. Heating was then stopped. 6 mL of cooled isopropanol (in an ice bath) was added in portions to the resulting solution. Upon addition of isopropanol, the substance immediately began to crystallize. The mixture was then stirred for 10 minutes and separated by vacuum filtration. The diastereomers A:B obtained were in a ratio of 95:5.

[0153] Example 27 - Preparation of pure diastereomer A-methanol / water

[0154] 300 mg of flonicamid was dissolved in 3 mL of methanol by heating to boiling point and stirring at 400 rpm. Heating was then stopped. 3 mL of cooled water (in an ice bath) was added in portions to the resulting solution. Upon addition of water, the substance immediately began to crystallize. After stirring for 10 minutes, the mixture was separated by vacuum filtration. The ratio of diastereomers A to B obtained was 95:5.

[0155] Example 28 - Preparation of pure diastereomer A - 96% ethanol / heptane

[0156] 506 mg of flonicamid was dissolved in 8 mL of 96% ethanol by heating to 60 °C and stirring at 400 rpm. Heating was then stopped. 16 mL of cooled heptane (in an ice bath) was added dropwise to the resulting solution over 30 minutes. Crystallization began after approximately 5 mL of heptane was added. 2 mL of the resulting suspension (product 1) was filtered after 5 minutes of crystallization. 4 mL of the suspension (product 2) was filtered after stirring at RT (400 rpm) for 3 hours. The diastereomeric ratios of products 1 and 2 were 94:6 and 95:5, respectively.

[0157] Example 29 - Preparation of pure diastereomer A-ethyl acetate / isopropanol

[0158] 300 mg of flonicamid was dissolved in 3 mL of ethyl acetate by heating to 60 °C and stirring at 400 rpm. Heating was then stopped. 12 mL of cooled isopropanol (in an ice bath) was added in portions to the resulting solution. No crystallization was observed after stirring for 1 hour. The solution was then cooled in an ice bath. Crystallization was observed within 5 minutes of stirring, followed by stirring for 10 minutes. The substance was separated by vacuum filtration. The ratio of diastereomers A:B obtained was 93:7.

[0159] Example 30 - Preparation of pure diastereomer A-acetone / tert-butyl methyl ether

[0160] 3000 mg of flonicamid was dissolved in 30 mL of acetone at 400 rpm at room temperature (RT). Then, 120 mL of tert-butyl methyl ether was added in portions. Crystallization was observed after stirring at room temperature for 2 minutes, and the stirring was maintained for 10 minutes. The substance was separated by vacuum filtration. The ratio of diastereomers A:B obtained was 92:8.

[0161] Example 31 - Preparation of pure diastereomer A-acetonitrile / water

[0162] 3000 mg of flonicamid was dissolved in 30 mL of acetonitrile by stirring at RT and 400 rpm. 60 mL of water was added in batches to the resulting solution while stirring at RT. Crystallization was observed during the addition of the antisolvent, and the solids were then separated by vacuum filtration. The ratio of diastereomers A:B obtained was 96:4.

[0163] 5. It is noteworthy that the method for preparing pure diastereomer A, as detailed above, effectively enables the acquisition of a stable product in a faster and easier manner compared to that currently known in the prior art. This aspect of the invention is particularly prominent compared to the slow, hot, and time-consuming methods taught, for example, in US 9,125,412, for converting diastereomer B to diastereomer A (see columns 31-32 therein).

[0164] Therefore, in one embodiment, the present invention relates to a stable pure diastereomer A product 10, which is produced by the method described and illustrated in detail in this invention.

[0165] Tables II-IV below summarize the solvents used in the different stages of the process detailed above for the production of Y-type, X-type crystals and pure diastereomer A.

[0166] Table II - Overview of Solvents for Y-type Crystals

[0167]

[0168] Table III - Overview of Solvents for Type X Crystals

[0169]

[0170]

[0171] Table IV - Overview of solvents for pure diastereomer A

[0172]

[0173] Experimental

[0174] 1. XRPD: The XRPD pattern was recorded at room temperature using copper Kα radiation on a PANalytical X'pertPro PW3040 / 60 powder diffractometer with Bragg-Brentano geometry and equipped with an X'celerator detector. The sample was prepared by mounting approximately 35 mg (slightly ground) of sample onto a cavity-equipped PW1818 / 32 Zero Background Holder and scanning from 3° to 40°2θ using the following acquisition parameters: generator pressure 45 kV, generator current 40 mA, step size 0.0167°, scan rate 0.05° / sec, number of steps 2214, and total time 12 min.

[0175] 2. DSC: DSC data is available on the Mettler Toledo DSC 822 equipped with a refrigeration system. e Collect the sample using a calorimeter. Place the sample (approximately 3-4 mg) into an aluminum DSC pan covered with a pinhole perforated cap. Heat the sample cell at a rate of 10 °C / min within a temperature range of 25 to 200 °C. Maintain nitrogen purging at a rate of 50 ml / min over the sample.

Claims

1. A composition of a stereoisomer of flonicamid, in, The stereoisomers are selected from diastereomers A and B. The diastereomers A and B are provided in a selected A:B ratio as a mixed crystal, and The composition is water-soluble, with a water solubility of at least about 0.70 ± 0.07 mg / ml.

2. The composition according to claim 1, wherein, The diastereomer A comprises a racemic mixture of the R,R and S,S enantiomers of the flupyradifurone. The hybrid crystal is a Y-type crystal comprising a type 1a crystal and a novel crystal phase. The Y-type type 1a hybrid crystal and the novel crystal phase are crystallized in proportion to produce a constant XRPD pattern.

3. The combination according to claim 2, wherein, The content of the crystal structure of the diastereomer A is 90% of the total content of the Y type, preferably 92%, more preferably 94%, and even more preferably 96% ± 1%.

4. The composition according to claim 2, wherein, The Y-type DSC temperature spectrum shows a melting peak with a maximum peak temperature in the range of 140-160℃.

5. The composition according to claim 2, wherein, The Y-type is characterized by XRPD peaks at 2θ values ​​of 15.5°, 16.3°, 17.4°, 19.2°, and 26.0° ± 0.2°.

6. The composition according to claim 5, wherein, A further characteristic of the Y-type is the XRPD peaks at θ values ​​of 19.4°, 20.0°, 21.3°, and 22.7° ± 0.2°.

7. The composition according to claim 2, wherein, The water solubility of the composition is about 1.2 ± 0.3 mg / ml.

8. The composition according to claim 1, wherein, The ratio A:B is between 3:7 and 2:

8. The mixed crystal of the diastereomers A and B is of type X, comprising type 1a and type 1b crystals.

9. The composition according to claim 8, wherein, The diastereomer B is a racemic mixture of the R,S and S,R enantiomers of flonicamid. The content of the diastereomer B is 60% to 80% of the total content of the composition, preferably 65% ​​to 75%, and more preferably 70%.

10. The composition according to claim 8, wherein, The characteristic of the X-type DSC temperature spectrum is the melting peak with a maximum peak temperature in the range of 114-119℃.

11. The composition according to claim 9, wherein, The water solubility of the composition is about 1.6 ± 0.3 mg / ml.

12. A composition comprising pure diastereomer A and at least 90%, preferably 94%, more preferably 96%, even more preferably 98%, even more preferably 99% ± 1% of said diastereomer A.

13. A method for preparing mixed crystals of Y, X and pure diastereomer A of flonicamid, said method comprising quenching, solvent-antisolvent, mother liquor evaporation and crystallization during a filtration process for crystallizing said forms of flonicamid.

14. The method according to claim 13, wherein, The method is a rapid cooling method, including: The raw material of flonicamid is dissolved in a solvent; Heating and stirring the solution of flonicamid; The solution was rapidly cooled in an ice bath at a temperature of 0 to 5°C; and The solution of flonicamid was prepared into a suspension; and Solid substances are separated from the suspension.

15. The method according to claim 14, wherein, The method is used to prepare the Y-type, wherein the solvent is selected from chloroform, toluene, and dichloroethane.

16. The method of claim 14, wherein, The method is used to prepare the X-type, wherein the solvent is isopropyl acetate, and wherein the method further includes: Filter the suspension; Evaporate the mother liquor to obtain a new suspension; and Solid substances are separated from the suspension.

17. The method according to claim 16, wherein, The separation of the solid material is selected from filtration, sedimentation and decantation, evaporation and centrifugation.

18. The method according to claim 14, wherein, The method is used to prepare pure diastereomer A with a content of 90%, preferably 94%, more preferably 96%, even more preferably 98%, even more preferably 99% ± 1% of the total content of flonicamid, wherein the solvent is selected from methanol, ethyl acetate and methyl isobutyl ketone.

19. The method according to claim 13, wherein, The method is a solvent-antisolvent method, including: The raw material of flonicamid is dissolved in a solvent by heating and stirring to form a solution containing the raw material of flonicamid. The antisolvent is added dropwise, and the antisolvent is cooled in an ice bath; and The antisolvent in the solution is stirred until the solid substance crystallizes.

20. The method according to claim 19, wherein, The addition of the antisolvent is carried out dropwise after the suspension has been cooled.

21. The method of claim 20, further comprising separating the crystal form from the suspension.

22. The method according to claim 21, wherein, The separation of the crystal form from the suspension is selected from filtering the crystal form, sedimentation and decantation, evaporation and centrifugation.

23. The method according to claim 13, wherein, The method is for preparing mother liquor evaporation of type X, wherein a solvent / antisolvent pair or a single solvent is used to form the mother liquor from which type X crystallizes, the solvent / antisolvent pair being selected from dichloromethane / heptane and 96% ethanol / water, and the solvent being selected from tert-butyl methyl ether, dichloroethane and isopropyl acetate.

24. The method according to claim 23, wherein, The mother liquor evaporation method includes: The raw material of flonicamid is dissolved in a solvent; Heating and stirring the solution of flonicamid; Cool the solution; After cooling, the antisolvent is added dropwise to the solution, wherein the antisolvent is cooled in an ice bath; The antisolvent is stirred into the solution until a suspension is formed; and Treating solid substances in the suspension; Evaporate the mother liquor and allow the new solid substance to crystallize in the suspension; and The new solid substance is separated from the suspension.

25. The method according to claim 23, wherein, The mother liquor evaporation method includes: Rapidly cool the solution of flonicamid; Stir until a suspension is formed; and Solid substances are treated in the suspension.

26. The method according to any one of claims 19 to 22, wherein, The method is used to prepare pure diastereomer A with a content of 90%, preferably 94%, more preferably 96%, even more preferably 98%, even more preferably 99% ± 1%, wherein the solvent is selected from acetone, acetonitrile, tetrahydrofuran, 96% ethanol, methanol and ethyl acetate, and the antisolvent is selected from water, tert-butyl methyl ether, water, isopropanol and heptane.

27. The method of claim 26, wherein, The pure diastereomer A is crystallized in type 1a crystals.

28. A composition comprising pure diastereomer A and at least 90%, preferably 94%, more preferably 96%, even more preferably 98%, even more preferably 99% ± 1% of said diastereomer A, said composition being produced by the method according to any one of claims 14 and 18 to 22.

29. A crystalline phase Yn, characterized in that... The main XRPD patterns are those of peaks with 2θ values ​​of 15.5°, 16.3°, 17.4°, 19.4°, and 22.7° ± 0.2°.

30. An insecticide and / or pesticide formulation comprising, alone, a crystalline mixture selected from flonicamid Y, X and pure diastereomer A, or together or in combination with other insecticides and pesticide compounds.

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