Process for the preparation of isoxazoline particles of large size

Abstract

To provide an isoxazoline compound-containing composition having a large size.SOLUTION: The composition containing the isoxazoline compound is prepared by a process for producing large isoxazoline compound particles, comprising initiating crystallization and then maintaining the temperature of crystallization in the metastable zone by removing, reheating and recycling a portion of the solvent, thereby causing existing crystals to grow larger while minimizing the formation of new, smaller crystals. Said composition is a composition comprising particles with a thickness greater than 10 μ m, preferably greater than 20 μ m, measured by scanning electron microscopy (SEM).SELECTED DRAWING: Figure 9

Description

[Technical Field]

[0001] Isoxazoline compounds are known in the art and these compounds and their antiparasitic properties are well known. Use as an insecticide is described, for example, in U.S. Patent Application No. US2007 / 0066617 and International Patent Application No. Patent applications WO2005 / 085216, WO2007 / 079162, WO2009 / 00 2809, WO2009 / 024541, WO2009 / 003075, WO2010 / 070068 and WO2010 / 079077, and the disclosures thereof and The references cited herein are incorporated by reference. Compounds of this type are ectoparasitic. against living organisms, namely parasitic insects such as fleas and ticks, and internal parasites such as mites and nematodes It is known to have excellent activity.

[0002] An example of an isoxazoline compound is carbamoylbenzamidophenylisoxazoline (CB Specific examples of CBPI compounds include 4-[5-(3,5-dichlorophenyl)- -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2- Methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benz Amide (CAS RN[864731-61-3])-USAN Fluralaner. [ka]

[0003] The CBPI compound fluralaner is disclosed in patent application WO2005 / 085216. Bravecto® is a treatment and prevention product for dogs for the treatment and control of fleas and ticks. It is a chewable tablet containing approved fluralaner (NADA 141-426, 201 (See May 15, 4).

[0004] Crystallization is a commonly used technique for the purification of chemicals and pharmaceutical substances. Separation of a solid from a liquid is a separation technique. A solid (solute) is mixed with a liquid solvent and stirred. When more solute is added to a solvent, the more reaches a point where the solute is insoluble in the solvent. This point is known as the saturation point, and the solution becomes saturated. For most substances, the amount of solute that dissolves in a solvent is a function of temperature. As the temperature increases, the amount of solute that can be dissolved increases. Some of the solute leaves the solution and solute crystals begin to form. The size of the crystals depends on the cooling rate. If the solution is cooled quickly, many small crystals will form. At slower cooling rates, larger crystals form. (Crystallization: Separation of Materials, 20 Accessed October 31, 2017, https: / / byjus.com / chemistr y / crystallization / ).

[0005] A theoretical explanation of the temperature dependence of crystal formation is presented below and illustrated in FIG.

[0006] "Let's say we start at point A on the diagram and are saturated. If we add Both crystals will dissolve. If you cool it to a point between A and B, the existing crystals will grow, but The solution enters a metastable region where no new crystals form. Further cooling results in an unstable solution at point B. where spontaneous formation of new crystals, i.e., nucleation, occurs. This causes the concentration The temperature decreases dramatically and reaches point C. Further cooling causes the crystals formed between B and C to grow. The supersaturation created by cooling is consumed. Therefore, the end of crystallization is reached at point D. Until then, it will remain in the metastable region. Source: "Practica in Process Engineering II Crystallography" Spring 2014 https: / / www.ethz.ch / conte nt / dam / ethz / special-interest / mavt / proces s-engineering / separation-processes-labor atory-dam / documents / practica%20in%20proc ess%20engineering%202 / crystallization.pd f, accessed December 19, 2017.

[0007] None of these documents discloses a method for controlling the particle size of isoxazoline compound crystals. There is no disclosure. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] US2007 / 0066617 issue [Patent Document 2] International Patent Publication No. WO2005 / 085216 [Patent Document 3] International Patent Publication No. WO2007 / 079162 [Patent Document 4] International Patent Publication No. WO2009 / 002809 [Patent Document 5] International Patent Publication No. WO2009 / 024541 [Patent Document 6] International Patent Publication No. WO2009 / 003075 [Patent Document 7] International Patent Publication No. WO2010 / 070068 [Patent Document 8] International Patent Publication No. WO2010 / 079077 Summary of the Invention

[0009] A method for producing isoxazoline compound particles, comprising: wherein the isoxazoline compound is represented by formula (I) [ka]

[0010] where: R 1 is a halogen, CF3, OCF3 or CN; n is an integer from 0 to 3; m is 1 or 2; R 2 is C1-C3 haloalkyl; T is a ring structure: a 5- or 6-membered ring, or a bicyclic ring, which is optionally substituted with one or more groups Y. and; Y is methyl, halomethyl, halogen, CN, NO2, NH2-C=S or Two adjacent Y groups join together to form a chain; Q is X-NR 3 R 4 , N.R. 5 -NR 6 -XR 3 , XR 3 or 5-membered N-heteroaryl a cyclic ring, which is optionally substituted with one or more groups; X is CH2, CH(CH3), CH(CN), CO, CS; R 3 is hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, meth oxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl ethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethy haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, Methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, proton cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, alkylsulfani alkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl kill, [ka] where Z A is hydrogen, halogen, cyano or halomethyl (CF3); R 4 is hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl methylcarbonyl, ethylcarbonyl, propylcarbonyl, propoxymethyl methylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, Aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, di Methoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl methylaminocarbonylmethyl or haloethylaminocarbonylethyl ; R 5 is H, alkyl or haloalkyl; R 6 is H, alkyl or haloalkyl; Or R 3 and R 4 together, [ka] forming a substituent selected from the group consisting of or a salt or solvate thereof, wherein the method comprises: a) The isoxazoline compound is dissolved in a crystallizer vessel using a temperature-dependent solubility with a solvent having the formula: b) Initiate crystallization by: i) cooling the crystallization vessel to supersaturation, or ii) shaking the crystallization vessel, or iii) adding seeds of an isoxazoline compound to the crystallization vessel; or iv) A combination of one or more of the above; c) removing a portion of the batch and heating the removed portion to dissolve the isoxazoline compound particles in the solvent; The dissolved isoxazoline compound solution is returned to the crystallization vessel; degree is equal to the removal rate, which is about 0.25 to 0.75 batch volumes per hour; and the batch volume is the volume of the isoxazoline compound solution produced in step a); and d) cooling the crystallization vessel to obtain isoxazoline compound particles of the desired size; Including, wherein the desired particle size is between 75 μm and 120 μm as measured by a light scattering device. Product-weighted particle size distribution (d50) and particle size distribution greater than 10 μm as measured by scanning electron microscopy The method is preferably a method in which the particles have an average particle thickness of more than 20 μm.

[0011] The diameter is greater than 10 μm, preferably less than 20 μm, as measured by scanning electron microscope (SEM). Large thickness and mechanical elasticity measured by pressure titration using Sympatec HELOS The isoxazoline compound particle composition containing particles having the above-mentioned property has a particle size distribution (d5 0) does not decrease by more than 40% from a dispersion pressure of 1 to 3 bar. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 shows the temperature dependence of crystal formation. [Figure 2] FIG. 2 shows the temperature dependence of the solubility of fluralaner in isopropanol (IPA). [Figure 3] FIG. 3 shows a schematic diagram of another configuration of the crystallization vessel and system. [Figure 4] FIG. 4 shows (3A) the particle size distribution of fluralaner crystals not produced by the method of the present invention; and (3B) an SEM image of the same crystals. [Figure 5] Figure 5 shows the pressure titration of Fluralaner crystals not produced by the method of the present invention. Sympatec pressure titration: As the pressure increases from 1 to 3 bar, the particle size (d50) decreases from 50 μm to 25 μm. This is material produced from an unoptimized recycle process. In this case, the crystals are thin and not mechanically robust, as can be seen from the pressure titration experiment. In this experiment, the x50 decreases from 110 μm at 1 bar to 80 μm at 2 bar and to 60 μm at 3 bar between the pressures dispersed at 1 bar and 3 bar, or a 46% decrease in size from 1 bar to 3 bar. [Figure 6] Figure 6 shows the particle size distribution and pressure titration of Fluralaner crystals produced by the method of the present invention. Sympatec pressure titration: As the pressure increases from 1 to 3 bar, the particle size (d50) decreases from 100 μm to 73 μm. [Figure 7] FIG. 7 shows the particle size distribution and pressure titration of fluralaner crystals produced by the method of the present invention. [Figure 8] FIG. 8 shows an SEM image of fluralaner crystals produced by a process other than that of the present invention. [Figure 9] FIG. 9 shows an SEM image of fluralaner crystals produced by the process of the present invention. [Figure 10]Figure 10 shows the particle size distribution of the material produced in Example 3. The resulting material had an x50 of 108, with a pressure titration of approximately 24% reduction in x50 from 1 bar to 3 bar. [Figure 11] FIG. 11 shows an SEM of the material prepared in Example 3. [Figure 12] FIG. 12 shows a schematic diagram of the pilot-scale equipment used in Example 4. [Figure 13] Figure 13 shows the particle size distribution of the material produced from Example 4. The resulting material had a d50 of 103 μm, a d10 of 47.3 μm, and a d90 of 158.8 μm. Particle size measurements for this sample were performed using a wet method using a Microtrac static light scattering system. [Figure 14] FIG. 14 shows an SEM of the material made from Example 4. [Figure 15] Figure 15 shows the particle size distribution of the material produced in Example 5. The resulting material had an average d50 of 99 μm, and pressure titration reduced the d50 by approximately 20% from 1 bar to 3 bar. [Figure 16] FIG. 16 shows an SEM of the material made from Example 5. DETAILED DESCRIPTION OF THE INVENTION

[0013] An improved method for producing large particles of isoxazoline compounds, comprising initiating crystallization and Then, a portion of the solvent is removed, reheated, and recycled to produce a mixture in the metastable region. Maintaining the crystallization temperature allows existing crystals to grow larger while new ones are formed. The method involves minimizing the formation of small crystals.

[0014] Crystallization is initiated by nucleation, which can occur spontaneously or by vibration or seed particles. Nucleation crystals are small crystals that form when the temperature of a saturated solution is lowered. Yes. If nucleation occurs too quickly, more and smaller crystals will grow.

[0015] For isoxazoline compounds, particularly fluralaner, the seed crystals are typically less than 10 μm long. is.

[0016] The crystallization process involves adding a nucleating agent (seed crystal) to a solution of an isoxazoline compound. The process begins with adding HCl to achieve the surface properties of the starting crystals that are easy to grow. When the solution is heated, a slurry of isoxazoline compound particles is formed in the solution. The growth rate is relatively high (52–100%) to promote a reasonable growth rate and avoid further nucleation. At lower temperatures, the growth rate is significantly slower and the risk of nucleation is greater. A portion of the batch of isoxazoline compound particle slurry is removed and heated to remove any formed The crystals are dissolved and returned to the crystallization vessel, where they are continuously supersaturated and crystal growth occurs. Under favorable growth conditions, thin plates are preferentially formed, which are susceptible to fracture. The recycling rate cannot be too slow. Under these conditions, neither nucleation nor agglomeration occurs. The recirculation rate should not be too high, as this can cause problems. As the temperature increases, the slurry is cooled at a rate that avoids nucleation to a temperature at which the desired crystal size is achieved. The dissolved isoxazoline compound solution is returned to the crystallization vessel after the isoxazoline compound is dissolved. Approximately 0.25 to 0.75 batch volumes per hour to achieve continuous crystal growth of the compound particles. This is done at a speed of

[0017] The slurry material is repeatedly removed and the dissolved isoxazoline is returned to the crystallization vessel. After sufficient particle size growth has been achieved, the crystallization vessel is left in the sintered state for 10 to 48 hours, preferably 12 to 18 hours. Cooling to about 0°C, preferably about -10°C, over a 20 hour period further reduces the supersaturation, and the desired Grow to the dimensions of.

[0018] Isoxazoline compounds having defined particle sizes produced by the process of the present invention Injectable compositions containing particles of the present invention exhibit desirable bioavailability and shelf life, while It has been found to cause minimal irritation at the injection site. provides a desirable safety profile for warm-blooded and avian recipients. Thus, a single dose of such a composition generally combats one or more parasites (e.g., ectoparasites, have been found to provide potent activity against insects such as fleas, ticks, or mites, while , rapid onset of activity, prolonged duration of activity, and / or a desirable safety profile. There is a tendency.

[0019] definition A scanning electron microscope (SEM) uses a focused beam of high-energy electrons to probe the surface of a solid sample. The signals are related to the external morphology (texture), chemical composition, and It reveals information about the sample, including the crystal structure and orientation of the materials that make up the sample.

[0020] A solvent with temperature-dependent solubility of a solute is one in which the solubility of the solute in the solvent changes with temperature. Generally, this means that solubility increases with increasing temperature.

[0021] The temperature sensitivity of the solubility of fluralaner in isopropanol (IPA) is shown in Figure 1. , the x-axis shows temperature and the y-axis shows the solubility of fluralaner expressed in mg / mL.

[0022] The metastable region of the solubility temperature curve is where existing crystals grow but no new crystals form. It is an area.

[0023] The crystallization vessel is the vessel in which crystallization occurs.

[0024] Saturation is the state of a solution when it holds the maximum equilibrium amount of dissolved substance at a given temperature.

[0025] Supersaturation is when a solution contains more solute than a saturated solution at equilibrium.

[0026] The slurry is a thin suspension.

[0027] The batch is the solvent plus solute.

[0028] The batch volume is the volume of the batch.

[0029] As used herein, the particle size data reported are based on static light scattering (laser diffraction) by conventional particle techniques known to those skilled in the art, such as particle size analysis (also called particle size separation), image analysis, or sieving. As measured, it is volume weighted. The details are shown below.

[0030] Mechanical elasticity refers to the ability of a crystal or particle to bend when subjected to pressure or other stresses. Mechanical resilience is the resistance of a material to breaking down into smaller crystals or particles. This device can measure particle size distribution simultaneously. In this experiment, pressure is applied to disperse or separate the crystals from each other. The change in particle size distribution measurement of d50 when the pressure is increased from 1 bar to 3 bar. Preferably, the particles of the isoxazoline compound of the present invention are dispersed at a dispersion pressure of 1 to 3 bar. When the particle size distribution measurement of d50 is increased to 1000 ppm, it should not decrease by more than 30-40%. stomach.

[0031] In embodiments of the isoxazoline for use in the present invention, T is selected from: [ka] TIFF2026001075000007.tif181170In this regard, in T-1, T-3 and T-4, the group Y is hydrogen, halogen, methyl, halome It is ethyl, ethyl or haloethyl.

[0032] In embodiments of the isoxazoline for use in the present invention, Q is selected from: [ka] where R 3 , R 4 , X and Z A is as defined above, and Z B teeth, [ka] and Z D teeth, [ka] is.

[0033] In one embodiment, the isoxazolines for use in the present invention are as shown in Table 1. be.

[0034] [Table 1] TIFF2026001075000012.tif98125TIFF2026001075000013.tif88125

[0035] In one embodiment, the isoxazolines for use in the present invention are as shown in Table 2. be.

[0036] [Table 2] TIFF2026001075000015.tif103125

[0037] In one embodiment, the isoxazoline for use in the present invention is the compound: [ka] and where R 1a , R 1b , R 1c are, independently of each other: hydrogen, Cl or CF3. Preferably, R 1a and R 1c is Cl or CF3, and R 1b is hydrogen and T is

[0038] [ka] where Y is methyl, bromine, Cl, F, CN, or C(S)NH2, and n=1 or 2; and Q is as defined above.

[0039] In an embodiment of the isoxazoline defined herein, R 3 is H, and R 4 is:-CH2-C(O)-NH-CH2-CF3, -CH2-C(O)-NH-CH 2-CH3, -CH2-CH2-CF3 or -CH2-CF3.

[0040] Isoxazolines for use in the present invention also include pharmaceutically acceptable salts, esters thereof. and / or N-oxides. In addition, references to isoxazoline compounds include polymorphic forms thereof. The term "stereoisomeric form" refers equally to any form or stereoisomer.

[0041] In terms of stereospecific form, the pharmaceutical composition according to the invention may be an isoquinoline derivative for use in the present invention. A racemic mixture of isoxazoline may be used, and the isoxazoline compounds as described above may be used. Alternatively, the pharmaceutical composition may contain equal amounts of the isomeric forms of the isomers as defined herein. Stereoisomeric enrichment in one of the enantiomers of sazoline compared to the racemic mixture Also, pharmaceutical compositions may be used containing isoxazoline compounds such as Essentially pure stereoisomers of the soxazoline compounds may also be used. Such enriched or purified stereoisomeric preparations of isoxazolines for this purpose are well known in the art. They can be prepared by known methods, for example, by catalytic asymmetric synthesis. or separation of diastereomeric salts (see, for example, WO2009 / 063910 and JP2011 / 051977, respectively.

[0042] In one embodiment of the pharmaceutical composition of the present invention, the isoxazoline is fluralaner, azolaner, The compound is one or more selected from the group consisting of foxolaner, lotilaner, and sarolaner.

[0043] In one embodiment, the compound of formula (I) is 4-[5-(3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamido Fluralaner (CAS RN864731-61-3-USAN).

[0044] In one embodiment, the fluralaner is S-fluralaner.

[0045] In another embodiment, the compound of formula (I) is a compound disclosed in WO2007 / 079162. 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro -5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[( 2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide ( CAS RN1093861-60-9, USAN-afoxolaner).

[0046] In one embodiment of the pharmaceutical composition according to the invention, the isoxazoline is lotilaner (CAS RN: 1369852-71-0; 3-methyl-N-[2-oxo-2-(2,2,2 -trifluoroethylamino)ethyl]-5-[(5S)-5-(3,4,5-trichloro (trifluorophenyl)-5-(trifluoromethyl)-4H-1,2-oxazol-3-yl] thiophene-2-carboxamide).

[0047] In one embodiment of the pharmaceutical composition according to the invention, the isoxazoline is sarolaner (CA S RN: 1398609-39-6; 1-(5'-((5S)-5-(3,5-dichloro (4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxo (3-sazolyl)-3'-H-spiro(azetidine-3,1'-(2)benzofura The compound is (methylsulfonyl)-1-yl-2-(methylsulfonyl)ethanone.

[0048] In another embodiment, the compound of formula (I) is (Z)-4-[5-(3,5-dichloro (phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -N-[(methoxyimino)methyl]-2-methylbenzamide (CAS RN 928 789-76-8).

[0049] In another embodiment, the compound of formula (I) is a compound of formula (I) disclosed in WO2009 / 0080250 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isothiazolinone [Soxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide (C AS RN1164267-94-0).

[0050] In one embodiment, the compounds of the present invention are the 5 -[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl )-3-Isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-thiazolinone) (trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide (CAS RN: 1231754-09-8).

[0051] One embodiment of the present invention is a method for preparing isoxazoline compound particles, wherein The soxazoline compound is a compound of formula (I), and the method comprises: a) The isoxazoline compound is dissolved in a crystallizer vessel using a temperature-dependent solubility combining with a solvent having b) heating the crystallization vessel until the isoxazoline compound dissolves in the solvent; c) Cool the crystallization vessel to 48-55°C and add the isoxazoline compound to the solvent. forming a titch; i) adding crystal seeds of an isoxazoline compound to a crystallization vessel to initiate crystallization and particle growth; Let it begin; ii) forming a slurry of isoxazoline compound particles and solvent in a crystallization vessel; d) maintaining the temperature of the crystallizer vessel at 48-55°C; e) Removing a portion of the batch and heating the removed portion to remove the isoxazoline compound particles. completely dissolved in the solvent; where the removal rate is about 0.25-0.75 batch volumes per hour. degrees; and wherein the batch volume is the amount of supersaturated isoxazoline produced in step c). is the volume of the compound solution; f) returning the dissolved isoxazoline compound solution to the crystallization vessel; wherein the return rate is e) is equal to the removal rate; and g) cooling the crystallization vessel to obtain isoxazoline compound particles of the desired size. Includes; wherein the desired particle size is between 75 μm and 120 μm as measured by a light scattering device. The volume weighted particle size distribution (d50) and the particle size distribution (particle size) are greater than 10 μm, preferably less than 20 μm. The grains have an average grain thickness greater than 10 ...

[0052] In one embodiment, the isoxazoline compound is fluralaner.

[0053] In one embodiment, the solvent is methanol or acetone. In one embodiment, the solvent is dimethyl acetate or acetonitrile. Dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethyl sulfoxide ( DMSO), N,N-diethyl ether-m-toluamide (DEET), 2-pyrrolidone , acetone, g-hexalactone, glycofurol (tetraglycol), methyl ethyl ketones, diethylene glycol monoethyl ether (Transcutol®), Ethyl lactate, dimethyl isosorbide, ethyl acetate, macrogol glycerol caprylic / capric triglyceride Labrasol®, dipropylene glycol monomethyl ether ( Dowanol (trademark DPM), glycerol formal, benzyl alcohol, methanol , polyethylene glycol 200, propylene carbonate, 1-methoxy-2-propyl Acetate (Dowanol brand PMA), Isopropylideneglycerol (Solketol ), ethyl alcohol, glycerol triacetate (triacetin), isopropyl alcohol Alcohol, propylene glycol, medium chain triglyceride (Miglyol Registered Trademark 812) , ethyl oleate, toluene, ethyl acetate or mixtures thereof.

[0054] In one embodiment, the solvent is isopropanol.

[0055] In one embodiment, the solvent is a mixture of toluene and ethyl acetate.

[0056] In one embodiment, the crystallization vessel of step b is heated to a temperature above 60°C, preferably about 65°C. is heated to

[0057] In one embodiment, in step c), the crystallization vessel is cooled to achieve supersaturation. Preferably, the mixture is cooled to a temperature of about 48 to 55°C, more preferably to a temperature of about 52 to 54°C. will be done.

[0058] In one embodiment, the removed portion is heated to a temperature above 60°C, preferably about 65°C. It is heated.

[0059] In one embodiment, the removed portion is heated via a heat exchanger or in a second vessel. can be.

[0060] In one embodiment, the removal rate in step e) is 0.40 to 0.46 batches per hour. It's volume.

[0061] In one embodiment, the removal rate is maintained for about 4 to 24 hours, preferably about 6 hours.

[0062] In one embodiment, the crystallization vessel of step g) is maintained at a temperature of about 0°C or below, preferably about -10°C. It is cooled gradually.

[0063] In an additional embodiment of any of the above methods, the isoxazoline compound particles of step g) are filtered. The method further comprises the step of:

[0064] In one embodiment, the temperature of the filtration is maintained below 0°C, preferably -10°C.

[0065] In one embodiment, the filtered isoxazoline particles are dried.

[0066] An embodiment of the present invention is an isoxazoline compound prepared by any of the methods disclosed herein. The particles are phosphorus compound particles.

[0067] One embodiment of the present invention is a method for manufacturing a semiconductor device having a thickness of less than 10 μm as measured by scanning electron microscope (SEM). Large particles, preferably greater than 20 μm thick, and Sympatec HELO Isoxazoline compounds containing particles with mechanical elasticity measured by pressure titration with S a particle composition, wherein the particle size distribution (d50) of the particles is It does not reduce power by more than 40%.

[0068] In one embodiment, the particle size distribution (d50) of the particles is determined from a dispersion pressure of 1 to 3 bar. The decrease will not be greater than 35%.

[0069] In one embodiment, the particle size distribution (d50) of the particles is determined from a dispersion pressure of 1 to 3 bar. The decrease will not be greater than 30%.

[0070] In one embodiment, the isoxazoline compound particle composition is observed under a scanning electron microscope (SEM ) is more than 10 μm and less than 100 μm, preferably more than 20 μm and less than 90 μm, This includes particles having a thickness of more than 30 μm and less than 80 μm.

[0071] In one embodiment, the isoxazoline compound particle composition is larger than 10 μm, preferably or particles with a thickness greater than 20 μm.

[0072] In one embodiment, the isoxazoline compound has a diameter of from about 25 microns to about 250 microns. particle size distribution, D50, from about 11 microns to about 2 microns, as measured by a static light scattering instrument; 50 micron particle size, about 50 microns to about 150 micron particle size, about 75 Particle size from microns to about 125 microns, particles from about 75 microns to about 150 microns particle size, about 90 microns to about 110 microns, or about 30 microns to It has a particle size of about 100 microns.

[0073] Particle size distribution describes the relative amount of particles present according to size. D10 is the D50 is the particle size distribution where 50% of the particles are smaller than the D90 is the particle size measurement distribution that represents the size at which 90% of the particles are smaller. 1 is a particle size measurement distribution representing the size of the particles.

[0074] In certain embodiments, the particle size D10 is about 10 μm, about 20 μm, about 30 μm, or about 40 μm. m, about 40 μm, about 50 μm, about 60 μm or about 80 μm.

[0075] In certain embodiments, the particle size D50 is about 50 μm, about 75 μm, about 80 μm, or about 90 μm. m, approx. 90 μm, approx. 100 μm, approx. 110 μm, approx. 120 μm, approx. 130 μm, approx. 140 μm or about 150 μm.

[0076] In certain embodiments, the particle size D90 is about 100 μm, about 130 μm, about 1 50 μm, about 175 μm, about 200 μm or about 250 μm.

[0077] In certain embodiments, the particle size D10 is about 20 to 35 μm, and the particle size The particle size D50 is about 90 to 105 μm, and the particle size D90 is about 155 to 160 μm. It is 175 μm.

[0078] In certain embodiments, the particle size D10 is about 25 to 30 μm, and the particle size The particle size D50 is about 95 to 100 μm, and the particle size D90 is about 160 to 180 μm. It is 170 μm.

[0079] In certain embodiments, the particle size D10 is about 10 to 20 μm, and the particle size The particle size D50 is about 85 to 110 μm, and the particle size D90 is about 170 to 180 μm. It is 185 μm.

[0080] In certain embodiments, the particle size D10 is about 10 to 15 μm, and the particle size The particle size D50 is about 95 to 105 μm, and the particle size D90 is about 175 to 180 μm. It is 180 μm.

[0081] In certain embodiments, the particle size D10 is about 10 to 25 μm, and the particle size The particle size D50 is about 40 to 60 μm, and the particle size D90 is about 95 to 10 0 μm.

[0082] In certain embodiments, the particle size D10 is about 15 to 20 μm, and the particle size The particle size D50 is about 45 to 55 μm, and the particle size D90 is about 90 to 95 μm. μm.

[0083] In certain embodiments, the particle size D10 is about 30 to 50 μm, and The particle size D50 is about 70 to 130 μm.

[0084] In certain embodiments, the particle size D10 is about 35 to 45 μm, and The particle size D50 is about 90 to 110 μm.

[0085] In certain embodiments, the particle size D10 is about 40 μm, and The D50 of the lens is approximately 100 μm.

[0086] Volume weighted particle size can be determined by sieving, microscopy or laser diffraction (Malvern or Symptom). Volume weighted particle size measurements can be performed using a Hydro 2000 G Malvern Mastersizer 2000 or Horiba with measuring cell This can be done using an LA-910 laser scattering particle size distribution analyzer. The product-weighted particle size can be measured by a Sympatec Helos instrument .

[0087] In one embodiment, the isoxazone compound is fluralaner. [Example]

[0088] Example 1 - Process for forming large particle size fluralanel Fluralaner was added at a concentration of 100 mg / mL in IPA, and 60 g of the solution was added to a 600 mL isotopically separated tube. The composition was heated to 65°C over 1 hour and aged for 1 hour to complete the reaction. The solution was cooled to 50°C over 20 minutes, and 0.6 g of crystalline flurara was added. The batch was cooled to 20°C over an additional 2 hours to establish the starting particles. The batch was heated to 54°C, at which point the batch stream was removed and the contents were allowed to completely dissolve. The removal rate and return rate to the crystallization vessel were adjusted to approximately 4.4-4. The recycle loop was run for 6 hours, at which point the x50 particle size was reached. The batch was aged at 54°C for 6 hours to further reduce the supersaturation, and then The mixture was cooled to 45°C over 6 hours, and then further cooled to 0°C over 16 hours. For a schematic diagram, see Figure 3. The resulting slurry was filtered and dried to obtain Fluralaner particles. The dried Fluralaner particles were measured to determine particle size and mechanical elasticity.

[0089] Example 2 - Measurement of particle size and mechanical elasticity of Fluralaner particles Volume-weighted particle size of fluralanel crystals measured by laser diffraction (Sympatec Helos) The particle size distribution was determined. Mechanical elasticity was also measured during the pressure titration experiments. Figure 4 shows the results of the present invention. FIG. 1 shows the particle size distribution of Fluralaner crystals not produced by the disclosed method. This material was isolated by unseeded crystallization from an ethyl acetate-toluene solvent system. It is a product of a conventional commercial process using the method. Of note is the small particle size, The particle size distribution is generally broad.

[0090] The fragile nature of the particles, which is not representative of the method of the present invention, is illustrated in FIG. 5, which shows the results of a pressure titration experiment. In this experiment, particles are exposed to increasing pressures from 1 bar to 3 bar. The particle size distribution was monitored. Figure 5 shows that the median particle size (d 50) decreased from 110 μm to 60 μm, representing a loss of approximately 45%. The distribution curve broadened and shifted towards smaller particle sizes. This is evidence of the particles breaking down under increased pressure, indicating that the particles were very thin.

[0091] In contrast, Figure 10 shows the particle size of fluralaner crystals produced by the method of the present invention. These particles have a larger d50 than the particles in Figure 5. Furthermore, the pressure drop In standard tests, for particles produced by the method of the present invention, the d50 was approximately 25% of the original value. This indicates that the mechanical resilience of these particles is increased. Also, under elevated pressure, the distribution changes from the unoptimized process shown in Figure 5 Also of note is the fact that the particles do not spread in the same manner as the particles of the present invention. 1 shows the particle size distribution and pressure titration of an additional batch of Fluralaner particles produced using this method. In this case, the original d50 of approximately 103 μm was reduced to approximately 67 μm, a loss of approximately 35%. 1 is a scanning electron microscope image of Fluralaner particles not produced by the method of the present invention. It is noteworthy that these crystals are quite thin. This is a scanning electron microscope image of the resulting Fluralaner particles. In contrast to the particles shown in Figure 8, These particles are large (approximately 100 μm) and thick (approximately 10–20 μm).

[0092] Examples 3-6: Process for forming large particle size fluralanel on an L-scale Fluralaner was added at a concentration of 100 mg / mL in isopropanol (IPA) for 60 min. 0 g was added to 6 L of isopropanol. This composition was heated to 65°C over 1 hour and The solution was cooled to 50°C over 20 minutes and 6 g of crystalline Fluralaner seeds were seeded, in this example unground seeds with a d50 of approximately 10 μm. The batch was cooled to 20°C over an additional 2 hours to establish the starting particles. Heat to 54°C, at which point 1.2 L of the batch is removed and all solids are completely dissolved. The recirculation loop was then started and the removal rate and crystallization volume were measured. The recycle loop lasted for 3 hours, and the return rate to the vessel was set at approximately 44-48 mL / min. At this point, the d50 particle size dimension is approximately 45 μm. The batch is aged at 54°C for 6 hours and then The mixture was further desaturated and then cooled to 45°C over 6 hours and then to 0°C over a further 16 hours. The resulting slurry was filtered and dried to obtain Fluralaner particles. The Ruralanel particles were measured to determine the particle size and to report the mechanical resilience of the particles, as shown in Figure 10. See Figure 11 for an SEM image of the resulting particles.

[0093] Example 4 - Pilot scale process for forming large particle size Fluralaner: Fluralaner was added at a concentration of 100 mg / mL in IPA, and 60 kg was added to a 600 L isolator. The composition was heated to 65°C over 1 hour and aged for 1 hour to complete the reaction. The solution was cooled to 50°C over 20 minutes and 600g of crystalline flurara was added. The flannel seeds were again inoculated with unground seeds having a d50 of approximately 10 μm. The batch was heated to 54°C and cooled to 20°C over 2 hours to establish the starting particles. At this point 120 L of the batch was removed and heated to high temperature (>65°C) until completely dissolved. The removal rate and the return rate to the crystallization vessel were set at approximately 4.4 to 4.8 L / min. The loop lasts for 2.75 hours, at which point the d50 particle size dimension is approximately 40 μm. The batch was aged at 54°C for 6 hours to further reduce the supersaturation, then cooled to 45°C over 6 hours. The mixture was then cooled to 0°C over a period of 16 hours. See Figure 12 for a schematic diagram of the process equipment. The resulting slurry was filtered and dried to obtain Fluralaner particles. The material was melted at low speed in a conical mill. The dried Fluralaner particles were measured and the particle size was The particle size and mechanical properties were determined. See Figure 13 for particle size distribution and mechanical properties. See Figure 14 for an SEM image of the resulting particles.

[0094] Example 5 - Formation of large particle size Fluralaner from an alternative solvent system: Fluralaner was dissolved in toluene:ethyl acetate 5:3 (by volume) at 100 mg / mL. The composition was heated to 65°C for 1 hour. The solution was heated and aged for 1 hour to allow complete dissolution. The solution was cooled to 50°C over 20 minutes. Seed with 0.6 g of fluralaner crystal seeds and again milled 10 μm d50. The batch was further cooled to 20°C over 2 hours to establish starting particles. The batch was heated to 54°C, at which point 120 mL of the batch was removed and allowed to dissolve completely. The removal rate and the return rate to the crystallization vessel were set at approximately 4.3 mL / The recycle loop lasted for 2.2 hours, at which point the x50 particle size dimension was The batch was aged at 54°C for 5 hours to further reduce the supersaturation, then The mixture was cooled to 45°C over 10 hours, and then further cooled to 0°C over 16 hours. The particle size and mechanical properties were determined using a Sympatec static light scattering system. See Figure 15 for particle size distribution and mechanical elasticity measured by pressure titration used See Figure 16 for SEM images of the resulting particles. These results are consistent with the results of the recirculation process. This shows that the target particle size and mechanical resilience can be achieved using this process. As can be seen, the solvent influences the morphology, and the surface of the crystals is larger for crystals grown from isopropanol. Note that the crystal surface is slightly modified.

Claims

1. A method for producing isoxazoline compound particles, comprising: Here, the isoxazoline compound is represented by the formula (I) 【Chemistry 1】 where: R １ is a halogen, CF ３ , OCF ３ or CN; n is an integer from 0 to 3; m is 1 or 2; R ２ is C １ -C ３ haloalkyl; T is a ring structure: a 5- or 6-membered ring, or a bicyclic ring, which is optionally substituted with one or more groups Y. and Y is methyl, halomethyl, halogen, CN, NO ２ , N.H. ２ -C=S or adjacent two adjacent Y groups together form a chain; Q is X-NR ３ R ４ , N.R. ５ -NR ６ -X-R ３ , X-R ３ , or five-membered N-heteroaryl a cyclohexyl ring, which is optionally substituted with one or more groups; X is CH ２ , CH(CH ３ ), CH(CN), CO, CS; R ３ is hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, meth oxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl ethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethyl haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, Methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, proton cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, alkylsulfani alkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl kill, 【Chemistry 2】 where Z Ａ is hydrogen, halogen, cyano or halomethyl (CF ３ ) and R ４ is hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl methylcarbonyl, ethylcarbonyl, propylcarbonyl, propoxymethyl methylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, Aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, di Methoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl methylaminocarbonylmethyl or haloethylaminocarbonylethyl ; R ５ is H, alkyl or haloalkyl; R ６ is H, alkyl or haloalkyl; Or, R ３ and R ４ together, 【Transformation 3】 forming a substituent selected from the group consisting of or a salt or solvate thereof, wherein the method comprises: a) The isoxazoline compound is added to a crystallizer vessel using a temperature-dependent solubility with a solvent having the formula: b) Initiate crystallization by: i) cooling the crystallization vessel to supersaturation, or ii) shaking the crystallization vessel, or iii) adding seeds of an isoxazoline compound to the crystallization vessel; or iv) A combination of one or more of the above; c) removing a portion of the batch and heating the removed portion to dissolve the isoxazoline compound particles in the solvent; The dissolved isoxazoline compound solution is returned to the crystallization vessel; The rate is equal to the removal rate, which is about 0.25 to 0.75 batch volumes per hour, and where: The batch volume is the volume of the isoxazoline compound solution produced in step a); and d) cooling the crystallization vessel to obtain isoxazoline compound particles of the desired size; Including, wherein the desired particle size is between 75 μm and 120 μm as measured by a light scattering device. Product weighted particle size distribution (d50) and particle size distribution greater than 10 μm as measured by scanning electron microscope The method for producing the particles preferably has an average particle thickness of more than 20 μm.

2. A method for producing isoxazoline compound particles, comprising: Here, the isoxazoline compound is represented by the formula (I) 【Chemistry 4】 where: R １ is a halogen, CF ３ , OCF ３ or CN; n is an integer from 0 to 3; m is 1 or 2; R ２ is C １ -C ３ haloalkyl; T is a ring structure: a 5- or 6-membered ring, or a bicyclic ring, which is optionally substituted with one or more groups Y. and Y is methyl, halomethyl, halogen, CN, NO ２ , N.H. ２ -C=S or adjacent two adjacent Y groups together form a chain; Q is X-NR ３ R ４ , N.R. ５ -NR ６ -X-R ３ , X-R ３ or 5-membered N-heteroaryl a cyclic ring, which is optionally substituted with one or more groups; X is CH ２ , CH(CH ３ ), CH(CN), CO, CS; R ３ is hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, meth oxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl ethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethyl haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, Methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, proton cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, alkylsulfani alkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl kill, 【Transformation 5】 and; Here, Z Ａ is hydrogen, halogen, cyano or halomethyl (CF ３ ) and R ４ is hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl methylcarbonyl, ethylcarbonyl, propylcarbonyl, propoxymethyl methylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, Aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, di Methoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl methylaminocarbonylmethyl or haloethylaminocarbonylethyl ; R ５ is hydrogen, alkyl or haloalkyl; R ６ is hydrogen, alkyl or haloalkyl; Or, R ３ and R ４ together, 【Transformation 6】 forming a substituent selected from the group consisting of or a salt or solvate thereof, wherein the method comprises: a) the temperature-dependent solubility of the isoxazoline compound and the isoxazoline compound in the crystallization vessel; with a solvent having b) heating the crystallization vessel until the isoxazoline compound dissolves in the solvent; c) Cool the crystallization vessel to 48-55°C to form a supersaturated isoxazoline compound in the solvent. forming a titch; i) Adding crystal seeds of an isoxazoline compound to a crystallization vessel to promote crystallization and particle growth. Start; ii) forming a slurry of isoxazoline compound particles and solvent in a crystallization vessel; d) maintaining the temperature of the crystallizer vessel at 48-55°C; e) Removing a portion of the batch and heating the removed portion to remove isoxazoline compound particles. completely dissolved in the solvent; wherein the removal rate is about 0.25 to 0.75 batch volumes per hour. degrees; and wherein the batch volume is the amount of supersaturated isoxazolinate produced in step c). is the volume of the mixture solution; f) returning the dissolved isoxazoline compound solution to the crystallization vessel; wherein the return rate is e) is equal to the removal rate of g) cooling the crystallization vessel to obtain isoxazoline compound particles of the desired size. Includes; wherein the desired particle size is between 75 μm and 120 μm as measured by a static light scattering device. and a volume weighted particle size distribution (d50) of 1 as measured by scanning electron microscopy (SEM). 0 μm, preferably greater than 20 μm, method.

3. 3. The method of claim 1, wherein the isoxazoline compound is fluralaner. 。

4. The process of any one of claims 1 to 3, wherein the solvent is isopropanol.

5. The crystallization vessel of step b is heated to a temperature above 60°C, preferably about 65°C. The method according to any one of claims 2 to 4.

6. 10. The method of claim 1, wherein the removed portion is heated to a temperature above 60°C, preferably about 65°C. The method described in any one of claims 1 to 5.

7. 7. The method of claim 1, wherein the removed portion is heated via a heat exchanger or in a second container.

10. The method according to any one of claims 1 to 9.

8. The removal rate in step e) is 0.40 to 0.46 batch volumes per hour.

8. The method according to any one of claims 7 to 7.

9. 9. Any of claims 1 to 8, wherein the removal rate is maintained for about 4 to 24 hours, preferably about 6 hours. The method described in claim 1.

10. The crystallization vessel of step g) is cooled to a temperature of about 0°C or below, preferably about -10°C. The method according to any one of claims 2 to 9.

11. 10. The method of claim 1, wherein the crystallization vessel is cooled over a period of 10 to 48 hours, preferably 12 to 20 hours.

11. The method according to any one of claims 1 to 10.

12. The method according to any one of claims 2 to 11, further comprising a step of filtering the isoxazoline compound particles of step g). The method described in any one of claims 1 to 4.

13. 13. The method of claim 12, wherein the temperature of the filtration is maintained below 0°C, preferably below -10°C.

14. The method according to any one of claims 12 to 13, wherein the filtered isoxazoline particles are dried. method.

15. Isoxazoline compound particles produced by the method according to any one of claims 1 to 14. 。

16. The diameter is greater than 10 μm, preferably greater than 20 μm, as measured by scanning electron microscope (SEM). An isoxazoline compound particle composition comprising particles of large thickness.

17. The mechanical modulus, measured by pressure titration, of the particles increased with increasing dispersion pressure from 1 to 3 bar. The volume-weighted particle size distribution (d50) measured by static light scattering equipment does not decrease by more than 40%. The isoxazoline compound particle composition according to claim 16, wherein the isoxazoline compound particle composition is free of hydroxybenzoates.

18. The isoxazoline compound according to claim 16 or 17, wherein the isoxazoline compound is fluralaner. Phosphorus compound particle composition.

19. The particle size distribution (d50) of the particles is reduced by more than 35% from dispersion pressures of 1 to 3 bar. The isoxazoline compound particle composition according to any one of claims 16 to 18, wherein the isoxazoline compound particle composition does not contain hydroxybenzoates.

20. The removal rate in step c) is 0.40 to 0.46 batch volumes per hour. The method according to claim 1.

21. The crystallization vessel of step d) is cooled to a temperature of about 0°C or below, preferably about -10°C. The method of claim 1.

22. The method of claim 1, further comprising the step of filtering the isoxazoline compound particles of step d). Law.

23. 22. The method of claim 21, wherein the temperature of the filtration is maintained below 0°C, preferably below -10°C.

24. 23. The process according to claim 21, wherein the filtered isoxazoline particles are dried. method.

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